Viral polymerase inhibitors

ABSTRACT

Compounds of formula I: 
                         
wherein X, R 2 , R 3 , R 5  and R 6  are defined herein, are useful as inhibitors of the hepatitis C virus NS5B polymerase.

RELATED APPLICATIONS

This application claims benefit of U.S. Ser. No. 60/822,711, filed Aug.17, 2006, which is herein incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to compounds, compositions and methods forthe treatment of hepatitis C virus (HCV) infection. In particular, thepresent invention provides novel inhibitors of the hepatitis C virusNS5B polymerase, pharmaceutical compositions containing such compoundsand methods for using these compounds in the treatment of HCV infection.

BACKGROUND OF THE INVENTION

It is estimated that at least 130 million persons worldwide are infectedwith the hepatitis C virus (HCV). Acute HCV infection progresses tochronic infection in a high number of cases, and, in some infectedindividuals, chronic infection leads to serious liver diseases such ascirrhosis and hepatocellular carcinoma.

Currently, standard treatment of chronic hepatitis C infection involvesadministration of pegylated interferon-alpha in combination withribavirin. However, this therapy is not effective in reducing HCV RNA toundetectable levels in many infected patients and is associated withoften intolerable side effects such as fever and other influenza-likesymptoms, depression, thrombocytopenia and hemolytic anemia.Furthermore, some HCV-infected patients have co-existing conditionswhich contraindicate this treatment.

Therefore, a need exists for alternative treatments for hepatitis Cviral infection. One possible strategy to address this need is thedevelopment of effective antiviral agents which inactivate viral or hostcell factors which are essential for viral replication.

HCV is an enveloped positive strand RNA virus in the genus Hepacivirusin the Flaviviridae family. The single strand HCV RNA genome isapproximately 9500 nucleotides in length and has a single open readingframe (ORF), flanked by 5′ and 3′ non-translated regions. The HCV 5′non-translated region is 341 nucleotides in length and functions as aninternal ribosome entry site for cap-independent translation initiation.The open reading frame encodes a single large polyprotein of about 3000amino acids which is cleaved at multiple sites by cellular and viralproteases to produce the mature structural and non-structural (NS2, NS3,NS4A, NS4B, NS5A, and NS5B) proteins. The viral NS2/3 protease cleavesat the NS2-NS3 junction; while the viral NS3 protease mediates thecleavages downstream of NS3, at the NS3-NS4A, NS4A-NS4B, NS4B-NS5A andNS5A-NS5B cleavage sites. The NS3 protein also exhibits nucleosidetriphosphatase and RNA helicase activities. The NS4A protein acts as acofactor for the NS3 protease and may also assist in the membranelocalization of NS3 and other viral replicase components. Although NS4Band the NS5A phosphoprotein are also likely components of the replicase,their specific roles are unknown. The NS5B protein is the elongationsubunit of the HCV replicase possessing RNA-dependent RNA polymerase(RdRp) activity.

The development of new and specific anti-HCV treatments is a highpriority, and virus-specific functions essential for replication are themost attractive targets for drug development. The absence of RNAdependent RNA polymerases in mammals, and the fact that this enzymeappears to be essential to viral replication, would suggest that theNS5B polymerase is an ideal target for anti-HCV therapeutics. It hasbeen recently demonstrated that mutations destroying NS5B activityabolish infectivity of RNA in a chimp model (Kolykhalov, A. A.; Mihalik,K.; Feinstone, S. M.; Rice, C. M.; 2000; J. Virol. 74: 2046-2051).

WO 03/004458 describes compounds of the general formula:

which modulate the activity of peroxisome proliferator-activatedreceptors α and/or γ. Similar compounds are described in Thor, M., etal, Bioorganic & Medicinal Chemistry Letters (2002) 12: 3565-3567;Östberg, T., et al, Journal of Biological Chemistry (2004) 279(39):41124-41130; and Hemalatha, R., et al, E-Journal of Chemistry (2004)1(5): 243-250 (abstracted in Chemical Abstracts 142: 190216).

SUMMARY OF THE INVENTION

The present invention provides a novel series of compounds havinginhibitory activity against HCV polymerase. In particular compoundsaccording to this invention inhibit RNA synthesis by the RNA dependentRNA polymerase of HCV, especially the enzyme NS5B encoded by HCV. Afurther advantage of compounds provided by this invention is their lowto very low or even non-significant activity against other polymerases.Further objects of this invention arise for the one skilled in the artfrom the following description and the examples.

One aspect of the invention provides compounds of formula (I):

wherein:

-   X is selected from O and S;-   R² is Het, optionally substituted with 1 to 5 R²⁰ substituents,    wherein R²⁰ in each case is independently selected from:    -   a) halo, cyano or nitro;    -   b) R⁷, —C(═O)—R⁷, —C(═O)—O—R⁷, —O—R⁷, —S—R⁷, —SO—R⁷,        —SO₂—R⁷—(C₁₋₆)alkylene-R⁷, —(C₁₋₆)alkylene-C(═O)—R⁷,        —(C₁₋₆)alkylene-C(═O)—O—R⁷, —(C₁₋₆)alkylene-O—R⁷,        —(C₁₋₆)alkylene-S—R⁷, —(C₁₋₆)alkylene-SO—R⁷ or        —(C₁₋₆)alkylene-SO₂—R⁷;        -   wherein R⁷ is in each instance independently selected from            H, (C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₂₋₆)alkynyl,            (C₁₋₆)haloalkyl, (C₃₋₇)cycloalkyl, aryl and Het; wherein the            (C₁₋₆)alkyl is optionally substituted with 1 or 2            substituents each independently selected from —OH,            —O—(C₁₋₆)alkyl, cyano, COOH, —NH₂, —NH(C₁₋₄)alkyl,            —NH(C₃₋₇)cycloalkyl, —N((C₁₋₄)alkyl)(C₃₋₇)cycloalkyl and            —N((C₁₋₄)alkyl)₂; and        -   wherein each of the aryl and Het is optionally substituted            with 1 to 3 substituents each independently selected from:        -   i) halo, cyano, oxo, thioxo, imino, —OH, —O—(C₁₋₆)alkyl,            —O—(C₁₋₆)haloalkyl, (C₃₋₇)cycloalkyl, (C₁₋₆)haloalkyl,            —C(═O)—(C₁₋₆)alkyl, —SO₂(C₁₋₆)alkyl, —C(═O)—NH₂,            —C(═O)—NH(C₁₋₄)alkyl, —C(═O)—N((C₁₋₄)alkyl)₂,            —C(═O)—NH(C₃₋₇)cycloalkyl,            —C(═O)—N((C₁₋₄)alkyl)(C₃₋₇)cycloalkyl, —NH₂, —NH(C₁₋₄)alkyl,            —N((C₁₋₄)alkyl)₂, —NH(C₃₋₇)cycloalkyl,            —N((C₁₋₄)alkyl)(C₃₋₇)cycloalkyl or —NH—C(═O)(C₁₋₄)alkyl;        -   ii) (C₁₋₆)alkyl optionally substituted with —OH,            —O—(C₁₋₆)haloalkyl, or —O—(C₁₋₆)alkyl; and        -   iii) aryl or Het, wherein each of the aryl and Het is            optionally substituted with halo or (C₁₋₆)alkyl; and    -   c) —N(R⁸)R⁹, —C(═O)—N(R⁸)R⁹, —O—C(═O)—N(R⁸)R⁹, —SO₂—N(R⁸)R⁹,        —(C₁₋₆)alkylene-N(R⁸)R⁹, —(C₁₋₆)alkylene-C(═O)—N(R⁸)R⁹,        —(C₁₋₆)alkylene-O—C(═O)—N(R⁸)R⁹, or —(C₁₋₆)alkylene-SO₂—N(R⁸)R⁹        wherein        -   R⁸ is in each instance independently selected from H,            (C₁₋₆)alkyl and (C₃₋₇)cycloalkyl; and        -   R⁹ is in each instance independently selected from R⁷,            —(C₁₋₆)alkylene-R⁷,            -   —SO₂—R⁷, —C(═O)—R⁷, —C(═O)OR⁷ and —C(═O)N(R⁸)R⁷; wherein                R⁷ and R⁸ are as defined above;-   R³ is selected from H, halo, (C₁₋₄)alkyl, —O—(C₁₋₄)alkyl,    —S—(C₁₋₄)alkyl, —NH₂, —NH(C₁₋₄)alkyl, —NH(C₃₋₇)cycloalkyl,    —N((C₁₋₄)alkyl)(C₃₋₇)cycloalkyl and —N((C₁₋₄)alkyl)₂;-   R⁵ is H, (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl or Het; the (C₁₋₆)alkyl and    Het each being optionally substituted with 1 to 4 substituents each    independently selected from (C₁₋₆)alkyl, Het, —OH, —COOH,    —C(═O)—(C₁₋₆)alkyl, —C(═O)—O—(C₁₋₆)alkyl, —SO₂(C₁₋₆)alkyl and    —C(═O)—N(R⁵¹)R⁵²;    -   wherein R⁵¹ is H, (C₁₋₆)alkyl or (C₃₋₇)cycloalkyl; and    -   R⁵² is H, (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, aryl, Het,        aryl-(C₁₋₃)alkyl- or Het-(C₁₋₃)alkyl-; wherein each of the        (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, aryl, Het, aryl-(C₁₋₃)alkyl- and        Het-(C₁₋₃)alkyl- are optionally substituted with 1 to 3        substituents each independently selected from (C₁₋₆)alkyl,        (C₁₋₆)haloalkyl, halo, oxo, —OH, —O(C₁₋₆)alkyl, —NH₂,        —NH(C₁₋₆)alkyl, —N((C₁₋₆)alkyl)₂, —NH(C₃₋₇)cycloalkyl,        —N((C₁₋₄)alkyl)(C₃₋₇)cycloalkyl, —C(═O)(C₁₋₆)alkyl and        —NHC(═O)—(C₁₋₆)alkyl;        -   wherein the (C₁₋₆)alkyl is optionally substituted with OH;    -   or R⁵¹ and R⁵², together with the N to which they are attached,        are linked to form a 4- to 7-membered heterocycle optionally        further containing 1 to 3 heteroatoms each independently        selected from N, O and S, wherein each S heteroatom may,        independently and where possible, exist in an oxidized state        such that it is further bonded to one or two oxygen atoms to        form the groups SO or SO₂;        -   wherein the heterocycle is optionally substituted with 1 to            3 substituents each independently selected from (C₁₋₆)alkyl,            (C₁₋₆)haloalkyl, halo, oxo, —OH, —O(C₁₋₆)alkyl, —NH₂,            —NH(C₁₋₆)alkyl, —N((C₁₋₆)alkyl)₂, —NH(C₃₋₇)cycloalkyl,            —N((C₁₋₄)alkyl)(C₃₋₇)cycloalkyl, —C(═O)(C₁₋₆)alkyl and            —NHC(═O)—(C₁₋₆)alkyl;            -   wherein the (C₁₋₆)alkyl is optionally substituted with                OH;    -   R⁶ is (C₃₋₇)cycloalkyl or aryl;        -   the (C₃₋₇)cycloalkyl and aryl each being optionally            substituted with 1 to 5 substituents each independently            selected from halo, (C₁₋₆)alkyl, (C₁₋₆)haloalkyl,            (C₃₋₇)cycloalkyl, —OH, —SH, —O—(C₁₋₄)alkyl and            —S—(C₁₋₄)alkyl; and    -   Het is a 4- to 7-membered saturated, unsaturated or aromatic        heterocycle having 1 to 4 heteroatoms each independently        selected from O, N and S, or a 7- to 14-membered saturated,        unsaturated or aromatic heteropolycycle having wherever possible        1 to 5 heteroatoms, each independently selected from O, N and S;        wherein each N heteroatom may, independently and where possible,        exist in an oxidized state such that it is further bonded to an        oxygen atom to form an N-oxide group and wherein each S        heteroatom may, independently and where possible, exist in an        oxidized state such that it is further bonded to one or two        oxygen atoms to form the groups SO or SO₂;    -   provided that when R² is selected from:

-   -   -   X is O; R³ is H; and R⁵ is H;        -   then R⁶ is not

or a salt or ester thereof.

Another aspect of this invention provides a compound of formula (I), ora pharmaceutically acceptable salt or ester thereof, as a medicament.

Still another aspect of this invention provides a pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof formula (I) or a pharmaceutically acceptable salt or ester thereof;and one or more pharmaceutically acceptable carriers.

According to an embodiment of this aspect, the pharmaceuticalcomposition according to this invention additionally comprises at leastone other antiviral agent.

The invention also provides the use of a pharmaceutical composition asdescribed hereinabove for the treatment of a hepatitis C viral infectionin a mammal having or at risk of having the infection.

A further aspect of the invention involves a method of treating ahepatitis C viral infection in a mammal having or at risk of having theinfection, the method comprising administering to the mammal atherapeutically effective amount of a compound of formula (I), apharmaceutically acceptable salt or ester thereof, or a compositionthereof as described hereinabove.

Another aspect of the invention involves a method of treating ahepatitis C viral infection in a mammal having or at risk of having theinfection, the method comprising administering to the mammal atherapeutically effective amount of a combination of a compound offormula (I) or a pharmaceutically acceptable salt or ester thereof, andat least one other antiviral agent; or a composition thereof.

Also within the scope of this invention is the use of a compound offormula (I) as described herein, or a pharmaceutically acceptable saltor ester thereof, for the treatment of a hepatitis C viral infection ina mammal having or at risk of having the infection.

Another aspect of this invention provides the use of a compound offormula (I) as described herein, or a pharmaceutically acceptable saltor ester thereof, for the manufacture of a medicament for the treatmentof a hepatitis C viral infection in a mammal having or at risk of havingthe infection.

An additional aspect of this invention refers to an article ofmanufacture comprising a composition effective to treat a hepatitis Cviral infection; and packaging material comprising a label whichindicates that the composition can be used to treat infection by thehepatitis C virus; wherein the composition comprises a compound offormula (I) according to this invention or a pharmaceutically acceptablesalt or ester thereof.

Still another aspect of this invention relates to a method of inhibitingthe replication of hepatitis C virus comprising exposing the virus to aneffective amount of the compound of formula (I), or a salt or esterthereof, under conditions where replication of hepatitis C virus isinhibited.

Further included in the scope of the invention is the use of a compoundof formula (I), or a salt or ester thereof, to inhibit the replicationof hepatitis C virus.

DETAILED DESCRIPTION OF THE INVENTION Definitions

As used herein, the following definitions apply unless otherwise noted:

The term “substituent”, as used herein and unless specified otherwise,is intended to mean an atom, radical or group which may be bonded to acarbon atom, a heteroatom or any other atom which may form part of amolecule or fragment thereof, which would otherwise be bonded to atleast one hydrogen atom. Substituents contemplated in the context of aspecific molecule or fragment thereof are those which give rise tochemically stable compounds, such as are recognized by those skilled inthe art.

The term “(C_(1-n))alkyl” as used herein, wherein n is an integer,either alone or in combination with another radical, is intended to meanacyclic, straight or branched chain alkyl radicals containing from 1 ton carbon atoms. “(C₁₋₆)alkyl” includes, but is not limited to, methyl,ethyl, propyl (n-propyl), butyl (n-butyl), 1-methylethyl (iso-propyl),1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl),1,1-dimethylethyl (tert-butyl), pentyl and hexyl. The abbreviation Medenotes a methyl group; Et denotes an ethyl group, Pr denotes a propylgroup, iPr denotes a 1-methylethyl group, Bu denotes a butyl group andtBu denotes a 1,1-dimethylethyl group.

The term “(C_(1-n))alkylene” as used herein, wherein n is an integer,either alone or in combination with another radical, is intended to meanacyclic, straight or branched chain divalent alkyl radicals containingfrom 1 to n carbon atoms. “(C₁₋₆)alkylene” includes, but is not limitedto,

The term “(C_(2-n))alkenyl”, as used herein, wherein n is an integer,either alone or in combination with another radical, is intended to meanan unsaturated, acyclic straight or branched chain radical containingtwo to n carbon atoms, at least two of which are bonded to each other bya double bond. Examples of such radicals include, but are not limitedto, ethenyl (vinyl), 1-propenyl, 2-propenyl, and 1-butenyl. Unlessspecified otherwise, the term “(C_(2-n))alkenyl” is understood toencompass individual stereoisomers where possible, including but notlimited to (E) and (Z) isomers, and mixtures thereof. When a (C_(2-n))alkenyl group is substituted, it is understood to be substituted on anycarbon atom thereof which would otherwise bear a hydrogen atom, unlessspecified otherwise, such that the substitution would give rise to achemically stable compound, such as are recognized by those skilled inthe art.

The term “(C_(2-n))alkynyl”, as used herein, wherein n is an integer,either alone or in combination with another radical, is intended to meanan unsaturated, acyclic straight or branched chain radical containingtwo to n carbon atoms, at least two of which are bonded to each other bya triple bond. Examples of such radicals include, but are not limitedto, ethynyl, 1-propynyl, 2-propynyl, and 1-butynyl. When a(C_(2-n))alkynyl group is substituted, it is understood to besubstituted on any carbon atom thereof which would otherwise bear ahydrogen atom, unless specified otherwise, such that the substitutionwould give rise to a chemically stable compound, such as are recognizedby those skilled in the art.

The term “(C_(3-m))cycloalkyl” as used herein, wherein m is an integer,either alone or in combination with another radical, is intended to meana cycloalkyl substituent containing from 3 to m carbon atoms andincludes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl.

The term “(C_(3-m))cycloalkyl-(C_(1-n))alkyl-” as used herein, wherein nand m are both integers, either alone or in combination with anotherradical, is intended to mean an alkyl radical having 1 to n carbon atomsas defined above which is itself substituted with a cycloalkyl radicalcontaining from 3 to m carbon atoms as defined above. Examples of(C₃₋₇)cycloalkyl-(C₁₋₆)alkyl- include, but are not limited to,cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl, 1-cyclopropylethyl, 2-cyclopropylethyl,1-cyclobutylethyl, 2-cyclobutylethyl, 1-cyclopentylethyl,2-cyclopentylethyl, 1-cyclohexylethyl and 2-cyclohexylethyl. When a(C_(3-m))cycloalkyl-(C_(1-n))alkyl- group is substituted, it isunderstood that substituents may be attached to either the cycloalkyl orthe alkyl portion thereof or both, unless specified otherwise.

The term “aryl” as used herein, either alone or in combination withanother radical, is intended to mean a carbocyclic aromatic monocyclicgroup containing 6 carbon atoms which may be further fused to a second5- or 6-membered carbocyclic group which may be aromatic, saturated orunsaturated. Aryl includes, but is not limited to, phenyl, indanyl,indenyl, 1-naphthyl, 2-naphthyl, tetrahydronaphthyl and dihydronaphthyl.

The term “aryl-(C_(1-n))alkyl-” as used herein, wherein n is an integer,either alone or in combination with another radical, is intended to meanan alkyl radical having 1 to n carbon atoms as defined above which isitself substituted with an aryl radical as defined above. Examples ofaryl-(C_(1-n))alkyl- include, but are not limited to, phenylmethyl(benzyl), 1-phenylethyl, 2-phenylethyl and phenylpropyl. When anaryl-(C_(1-n))alkyl- group is substituted, it is understood thatsubstituents may be attached to either the aryl or the alkyl portionthereof or both, unless specified otherwise.

The term “Het” as used herein, either alone or in combination withanother radical, is intended to mean a 4- to 7-membered saturated,unsaturated or aromatic heterocycle having 1 to 4 heteroatoms eachindependently selected from O, N and S, or a 7- to 14-memberedsaturated, unsaturated or aromatic heteropolycycle having whereverpossible 1 to 5 heteroatoms, each independently selected from O, N andS; wherein each N heteroatom may, independently and where possible,exist in an oxidized state such that it is further bonded to an oxygenatom to form an N-oxide group and wherein each S heteroatom may,independently and where possible, exist in an oxidized state such thatit is further bonded to one or two oxygen atoms to form the groups SO orSO₂, unless specified otherwise. When a Het group is substituted, it isunderstood that substituents may be attached to any carbon atom orheteroatom thereof which would otherwise bear a hydrogen atom, unlessspecified otherwise.

The term “Het-(C_(1-n))alkyl-” as used herein and unless specifiedotherwise, wherein n is an integer, either alone or in combination withanother radical, is intended to mean an alkyl radical having 1 to ncarbon atoms as defined above which is itself substituted with a Hetsubstituent as defined above. Examples of Het-(C_(1-n))alkyl- include,but are not limited to, thienylmethyl, furylmethyl, piperidinylethyl,2-pyridinylmethyl, 3-pyridinylmethyl, 4-pyridinylmethyl,quinolinylpropyl, and the like. When a Het-(C_(1-n))alkyl- group issubstituted, it is understood that substituents may be attached toeither the Het or the alkyl portion thereof or both, unless specifiedotherwise.

The term “heteroatom” as used herein is intended to mean O, S or N.

The term “heterocycle” as used herein and unless specified otherwise,either alone or in combination with another radical, is intended to meana 4- to 7-membered saturated, unsaturated or aromatic heterocyclecontaining from 1 to 4 heteroatoms each independently selected from O, Nand S; or a monovalent radical derived by removal of a hydrogen atomtherefrom. Examples of such heterocycles include, but are not limitedto, azetidine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene,thiazolidine, oxazolidine, pyrrole, thiophene, furan, pyrazole,imidazole, isoxazole, oxazole, isothiazole, thiazole, triazole,tetrazole, piperidine, piperazine, azepine, diazepine, pyran,1,4-dioxane, 4-morpholine, 4-thiomorpholine, pyridine, pyridine-N-oxide,pyridazine, pyrazine, pyrimidine, and the following heterocycles:

and saturated, unsaturated and aromatic derivatives thereof.

The term “heteropolycycle” as used herein and unless specifiedotherwise, either alone or in combination with another radical, isintended to mean a heterocycle as defined above fused to one or moreother cycle, including a carbocycle, a heterocycle or any other cycle;or a monovalent radical derived by removal of a hydrogen atom therefrom.Examples of such heteropolycycles include, but are not limited to,indole, isoindole, benzimidazole, benzothiophene, benzofuran,benzodioxole, benzothiazole, quinoline, isoquinoline, naphthyridine, andthe following heteropolycycles:

and saturated, unsaturated and aromatic derivatives thereof.

The term “halo” as used herein is intended to mean a halogen substituentselected from fluoro, chloro, bromo or iodo.

The term “(C_(1-n))haloalkyl” as used herein, wherein n is an integer,either alone or in combination with another radical, is intended to meanan alkyl radical having 1 to n carbon atoms as defined above wherein oneor more hydrogen atoms are each replaced by a halo substituent. Examplesof (C_(1-n))haloalkyl include but are not limited to chloromethyl,chloroethyl, dichloroethyl, bromomethyl, bromoethyl, dibromoethyl,fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl anddifluoroethyl.

The terms “—O—(C_(1-n))alkyl” or “(C_(1-n))alkoxy” as used hereininterchangeably, wherein n is an integer, either alone or in combinationwith another radical, is intended to mean an oxygen atom further bondedto an alkyl radical having 1 to n carbon atoms as defined above.Examples of —O—(C_(1-n))alkyl include but are not limited to methoxy(CH₃O—), ethoxy (CH₃CH₂O—), propoxy (CH₃CH₂CH₂O—), 1-methylethoxy(iso-propoxy; (CH₃)₂CH—O—) and 1,1-dimethylethoxy (tert-butoxy;(CH₃)₃C—O—). When an —O—(C_(1-n))alkyl radical is substituted, it isunderstood to be substituted on the (C_(1-n))alkyl portion thereof.

The terms “—S—(C_(1-n))alkyl” or “(C_(1-n))alkylthio” as used hereininterchangeably, wherein n is an integer, either alone or in combinationwith another radical, is intended to mean an sulfur atom further bondedto an alkyl radical having 1 to n carbon atoms as defined above.Examples of —S—(C_(1-n))alkyl include but are not limited to methylthio(CH₃S—), ethylthio (CH₃CH₂S—), propylthio (CH₃CH₂CH₂S—),1-methylethylthio (isopropylthio; (CH₃)₂CH—S—) and 1,1-dimethylethylthio(tert-butylthio; (CH₃)₃C—S—). When —S—(C_(1-n))alkyl radical, or anoxidized derivative thereof, such as an —SO—(C_(1-n))alkyl radical or an—SO₂—(C_(1-n))alkyl radical, is substituted, each is understood to besubstituted on the (C_(1-n))alkyl portion thereof.

The term “oxo” as used herein is intended to mean an oxygen atomattached to a carbon atom as a substituent by a double bond (═O).

The term “thioxo” as used herein is intended to mean a sulfur atomattached to a carbon atom as a substituent by a double bond (═S).

The term “imino” as used herein is intended to mean a NH group attachedto a carbon atom as a substituent by a double bond (═NH).

The term “COOH” as used herein is intended to mean a carboxyl group(—C(═O)—OH). It is well known to one skilled in the art that carboxylgroups may be substituted by functional group equivalents. Examples ofsuch functional group equivalents contemplated in this inventioninclude, but are not limited to, esters, amides, imides, boronic acids,phosphonic acids, phosphoric acids, tetrazoles, triazoles,N-acylsulfamides (RCONHSO₂NR₂), and N-acylsulfonamides (RCONHSO₂R).

The term “functional group equivalent” as used herein is intended tomean an atom or group that may replace another atom or group which hassimilar electronic, hybridization or bonding properties.

The term “protecting group” as used herein is intended to meanprotecting groups that can be used during synthetic transformation,including but not limited to examples which are listed in Greene,“Protective Groups in Organic Chemistry”, John Wiley & Sons, New York(1981), and more recent editions thereof, herein incorporated byreference.

The following designation

is used in sub-formulas to indicate the bond which is connected to therest of the molecule as defined.

The term “salt thereof” as used herein is intended to mean any acidand/or base addition salt of a compound according to the invention,including but not limited to a pharmaceutically acceptable salt thereof.

The term “pharmaceutically acceptable salt” as used herein is intendedto mean a salt of a compound according to the invention which is, withinthe scope of sound medical judgment, suitable for use in contact withthe tissues of humans and lower animals without undue toxicity,irritation, allergic response, and the like, commensurate with areasonable benefit/risk ratio, generally water or oil-soluble ordispersible, and effective for their intended use. The term includespharmaceutically-acceptable acid addition salts andpharmaceutically-acceptable base addition salts. Lists of suitable saltsare found in, for example, S. M. Birge et al., J. Pharm. Sci., 1977, 66,pp. 1-19, herein incorporated by reference.

The term “pharmaceutically-acceptable acid addition salt” as used hereinis intended to mean those salts which retain the biologicaleffectiveness and properties of the free bases and which are notbiologically or otherwise undesirable, formed with inorganic acidsincluding but not limited to hydrochloric acid, hydrobromic acid,sulfuric acid, sulfamic acid, nitric acid, phosphoric acid and the like,and organic acids including but not limited to acetic acid,trifluoroacetic acid, adipic acid, ascorbic acid, aspartic acid,benzenesulfonic acid, benzoic acid, butyric acid, camphoric acid,camphorsulfonic acid, cinnamic acid, citric acid, digluconic acid,ethanesulfonic acid, glutamic acid, glycolic acid, glycerophosphoricacid, hemisulfic acid, hexanoic acid, formic acid, fumaric acid,2-hydroxyethanesulfonic acid (isethionic acid), lactic acid,hydroxymaleic acid, malic acid, malonic acid, mandelic acid,mesitylenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid,nicotinic acid, 2-naphthalenesulfonic acid, oxalic acid, pamoic acid,pectinic acid, phenylacetic acid, 3-phenylpropionic acid, pivalic acid,propionic acid, pyruvic acid, salicylic acid, stearic acid, succinicacid, sulfanilic acid, tartaric acid, p-toluenesulfonic acid, undecanoicacid and the like.

The term “pharmaceutically-acceptable base addition salt” as used hereinis intended to mean those salts which retain the biologicaleffectiveness and properties of the free acids and which are notbiologically or otherwise undesirable, formed with inorganic basesincluding but not limited to ammonia or the hydroxide, carbonate, orbicarbonate of ammonium or a metal cation such as sodium, potassium,lithium, calcium, magnesium, iron, zinc, copper, manganese, aluminum andthe like. Particularly preferred are the ammonium, potassium, sodium,calcium, and magnesium salts. Salts derived frompharmaceutically-acceptable organic nontoxic bases include but are notlimited to salts of primary, secondary, and tertiary amines, quaternaryamine compounds, substituted amines including naturally occurringsubstituted amines, cyclic amines and basic ion-exchange resins, such asmethylamine, dimethylamine, trimethylamine, ethylamine, diethylamine,triethylamine, isopropylamine, tripropylamine, tributylamine,ethanolamine, diethanolamine, 2-dimethylaminoethanol,2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine,caffeine, hydrabamine, choline, betaine, ethylenediamine, glucosamine,methylglucamine, theobromine, purines, piperazine, piperidine,N-ethylpiperidine, tetramethylammonium compounds, tetraethylammoniumcompounds, pyridine, N,N-dimethylaniline, N-methylpiperidine,N-methylmorpholine, dicyclohexylamine, dibenzylamine,N,N-dibenzylphenethylamine, 1-ephenamine, N,N′-dibenzylethylenediamine,polyamine resins and the like. Particularly preferred organic nontoxicbases are isopropylamine, diethylamine, ethanolamine, trimethylamine,dicyclohexylamine, choline, and caffeine.

The term “ester thereof” as used herein is intended to mean any ester ofa compound according to the invention in which any of the —COOHsubstituents of the molecule is replaced by a —COOR substituent, inwhich the R moiety of the ester is any carbon-containing group whichforms a stable ester moiety, including but not limited to alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,heterocyclyl, heterocyclylalkyl, each of which being optionally furthersubstituted. The term “ester thereof” includes but is not limited topharmaceutically acceptable esters thereof.

The term “pharmaceutically acceptable ester” as used herein is intendedto mean esters of the compound according to the invention in which anyof the COOH substituents of the molecule are replaced by a —COORsubstituent, in which the R moiety of the ester is selected from alkyl(including, but not limited to, methyl, ethyl, propyl, 1-methylethyl,1,1-dimethylethyl, butyl); alkoxyalkyl (including, but not limited tomethoxymethyl); acyloxyalkyl (including, but not limited toacetoxymethyl); arylalkyl (including, but not limited to, benzyl);aryloxyalkyl (including, but not limited to, phenoxymethyl); and aryl(including, but not limited to phenyl) optionally substituted withhalogen, (C₁₋₄)alkyl or (C₁₋₄)alkoxy. Other suitable esters can be foundin Design of Prodrugs, Bundgaard, H. Ed. Elsevier (1985), hereinincorporated by reference. Such pharmaceutically acceptable esters areusually hydrolyzed in vivo when injected into a mammal and transformedinto the acid form of the compound according to the invention. Withregard to the esters described above, unless otherwise specified, anyalkyl moiety present preferably contains 1 to 16 carbon atoms, morepreferably 1 to 6 carbon atoms. Any aryl moiety present in such esterspreferably comprises a phenyl group. In particular the esters may be a(C₁₋₁₆)alkyl ester, an unsubstituted benzyl ester or a benzyl estersubstituted with at least one halogen, (C₁₋₆)alkyl, (C₁₋₆)alkoxy, nitroor trifluoromethyl.

The term “mammal” as used herein is intended to encompass humans, aswell as non-human mammals which are susceptible to infection byhepatitis C virus. Non-human mammals include but are not limited todomestic animals, such as cows, pigs, horses, dogs, cats, rabbits, ratsand mice, and non-domestic animals.

The term “treatment” as used herein is intended to mean theadministration of a compound or composition according to the presentinvention to alleviate or eliminate symptoms of the hepatitis C diseaseand/or to reduce viral load in a patient. The term “treatment” alsoencompasses the administration of a compound or composition according tothe present invention post-exposure of the individual to the virus butbefore the appearance of symptoms of the disease, and/or prior to thedetection of the virus in the blood, to prevent the appearance ofsymptoms of the disease and/or to prevent the virus from reachingdetectable levels in the blood.

The term “therapeutically effective amount” means an amount of acompound according to the invention, which when administered to apatient in need thereof, is sufficient to effect treatment fordisease-states, conditions, or disorders for which the compounds haveutility. Such an amount would be sufficient to elicit the biological ormedical response of a tissue system, or patient that is sought by aresearcher or clinician. The amount of a compound according to theinvention which constitutes a therapeutically effective amount will varydepending on such factors as the compound and its biological activity,the composition used for administration, the time of administration, theroute of administration, the rate of excretion of the compound, theduration of the treatment, the type of disease-state or disorder beingtreated and its severity, drugs used in combination with orcoincidentally with the compounds of the invention, and the age, bodyweight, general health, sex and diet of the patient. Such atherapeutically effective amount can be determined routinely by one ofordinary skill in the art having regard to their own knowledge, thestate of the art, and this disclosure.

The term “antiviral agent” as used herein is intended to mean an agentthat is effective to inhibit the formation and/or replication of a virusin a mammal, including but not limited to agents that interfere witheither host or viral mechanisms necessary for the formation and/orreplication of a virus in a mammal.

PREFERRED EMBODIMENTS

In the following preferred embodiments, groups and substituents of thecompounds according to this invention are described in detail.

-   X:-   X-A: In one embodiment, X is O.-   X-B: In another embodiment, X is S.

Any and each individual definition of X as set out herein may becombined with any and each individual definition of R², R³, R⁵ and R⁶ asset out herein.

-   R²:-   Het-A: In one embodiment, R² is Het wherein Het is a 5- or    6-membered heterocycle containing 1 to 3 heteroatoms each    independently selected from O, N and S, or a 9- or 10-membered    bicyclic heteropolycycle containing 1 to 3 heteroatoms each    independently selected from O, N and S; wherein Het is optionally    substituted with 1 to 5 R²⁰ substituents, wherein R²⁰ is as defined    herein.-   Het-B: In another embodiment, R² is Het wherein Het is a 5- or    6-membered aromatic heterocycle containing 1 or 2 N heteroatoms, or    a 9- or 10-membered bicyclic heteropolycycle containing 1 or 2 N    heteroatoms; wherein Het is optionally substituted with 1 to 3 R²⁰    substituents, wherein R²⁰ is as defined herein.-   Het-C: In another embodiment, R² is Het selected from the following    formulas:

-   -   wherein Het is optionally substituted with 1 to 3 R²⁰        substituents, wherein R²⁰ is as defined herein.

-   Het-D: In another embodiment, R² is Het of the formula:

-   -   wherein Het is optionally substituted with 1 to 3 R²⁰        substituents, wherein R²⁰ is as defined herein.

-   Het-E: In another embodiment, R² is a group of the formula:

-   -   wherein R²³ is R²⁰ as defined herein.

-   R²⁰-A: In one embodiment, R²⁰ is selected from:    -   a) halo, cyano or nitro;    -   b) R⁷, —(C₁₋₆)alkylene-R⁷, —C(═O)—R⁷, —O—R⁷, —C(═O)—O—R⁷,        —(C₁₋₆)alkylene-O—R⁷, —S—R⁷, —SO₂—R⁷, —(C₁₋₆)alkylene-S—R⁷ or        —(C₁₋₆)alkylene-SO₂—R⁷;        -   wherein R⁷ is in each instance independently selected from            H, (C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₁₋₆)haloalkyl,            (C₃₋₇)cycloalkyl, aryl and Het; wherein the Het is a 5- or            6-membered heterocycle containing 1 to 4 heteroatoms, each            independently selected from N, O and S, or Het is a 9- or            10-membered heteropolycycle containing 1 to 4 heteroatoms,            each independently selected from N, O and S; wherein each N            heteroatom may, independently and where possible, exist in            an oxidized state such that it is further bonded to an            oxygen atom to form an N-oxide group and wherein each S            heteroatom may, independently and where possible, exist in            an oxidized state such that it is further bonded to one or            two oxygen atoms to form the groups SO or SO₂; and        -   wherein the (C₁₋₆)alkyl is optionally substituted with 1 or            2 substituents each independently selected from —OH,            —O—(C₁₋₆)alkyl and COOH; and wherein each of the aryl and            Het is optionally substituted with 1 to 3 substituents each            independently selected from halo, cyano, oxo, imino, —OH,            —O—(C₁₋₆)alkyl, —NH₂, —NH(C₁₋₄)alkyl, —N((C₁₋₄)alkyl)₂,            —NH—C(═O)(C₁₋₄)alkyl, (C₁₋₆)alkyl and Het, wherein the Het            is a 5- or 6-membered heterocycle containing 1 to 4            heteroatoms, each independently selected from N, O and S;            and    -   c) —N(R⁸)R⁹, —(C₁₋₆)alkylene-N(R⁸)R⁹ or        —(C₁₋₆)alkylene-C(═O)—N(R⁸)R⁹ wherein        -   R⁸ is in each instance independently selected from H and            (C₁₋₆)alkyl; and        -   R⁹ is in each instance independently selected from R⁷,            —SO₂—R⁷, —C(═O)—R⁷, —C(═O)OR⁷ and —C(═O)N(R⁸)R⁷; wherein R⁷            and R⁸ are as defined above.

-   R²⁰-B: In another embodiment, R²⁰ is selected from:    -   a) halo or cyano;    -   b) R⁷, —(C₁₋₆)alkylene-R⁷, —C(═O)—R⁷, —(C₁₋₆)alkylene-O—R⁷,        —SO₂—R⁷, —(C₁₋₆)alkylene-S—R⁷ or —(C₁₋₆)alkylene-SO₂—R⁷;        -   wherein R⁷ is in each instance independently selected from            H, (C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₁₋₆)haloalkyl,            (C₃₋₇)cycloalkyl, aryl and Het; wherein the Het is a 5- or            6-membered heterocycle containing 1 to 4 heteroatoms, each            independently selected from N, O and S, or Het is a 9- or            10-membered heteropolycycle containing 1 to 4 heteroatoms,            each independently selected from N, O and S; wherein each N            heteroatom may, independently and where possible, exist in            an oxidized state such that it is further bonded to an            oxygen atom to form an N-oxide group and wherein each S            heteroatom may, independently and where possible, exist in            an oxidized state such that it is further bonded to one or            two oxygen atoms to form the groups SO or SO₂; and        -   wherein the (C₁₋₆)alkyl is optionally substituted with 1 or            2 substituents each independently selected from —OH,            —O—(C₁₋₆)alkyl and COOH; and wherein each of the aryl and            Het is optionally substituted with 1 to 3 substituents each            independently selected from halo, cyano, oxo, imino, —OH,            —O—(C₁₋₆)alkyl, —NH₂, —NH(C₁₋₄)alkyl, —N((C₁₋₄)alkyl)₂,            —NH—C(═O)(C₁₋₄)alkyl, (C₁₋₆)alkyl and Het, wherein the Het            is a 5- or 6-membered heterocycle containing 1 to 4            heteroatoms, each independently selected from N, O and S;            and    -   c) —(C₁₋₆)alkylene-N(R⁸)R⁹ or —(C₁₋₆)alkylene-C(═O)—N(R⁸)R⁹        wherein        -   R⁸ is in each instance independently selected from H and            (C₁₋₆)alkyl; and        -   R⁹ is in each instance independently selected from R⁷,            —SO₂—R⁷, —C(═O)—R⁷, —C(═O)OR⁷ and —C(═O)N(R⁸)R⁷; wherein R⁷            and R⁸ are as defined above.

-   R²⁰-C: In another embodiment, R²⁰ is selected from:    -   a) halo or cyano;    -   b) R⁷, —CH₂—R⁷, —C(═O)—R⁷, —CH₂—O—R⁷, —SO₂—R⁷, —CH₂—S—R⁷ or        —CH₂—SO₂—R⁷; wherein R⁷ is in each instance independently        selected from H, (C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₁₋₆)haloalkyl,        (C₃₋₇)cycloalkyl, phenyl and Het; wherein the Het is selected        from:

-   -   -   wherein the (C₁₋₆)alkyl is optionally substituted with 1 or            2 substituents each independently selected from —OH,            —O—(C₁₋₆)alkyl and COOH; and wherein each of the phenyl and            Het is optionally substituted with 1 to 3 substituents each            independently selected from halo, cyano, oxo, imino, —OH,            —O—(C₁₋₆)alkyl, —NH₂, —NH(C₁₋₄)alkyl, —N((C₁₋₄)alkyl)₂,            —NH—C(═O)(C₁₋₄)alkyl, (C₁₋₆)alkyl and

-   -   -   and

    -   c) —CH₂—N(R⁸)R⁹ or —CH₂—C(═O)—N(R⁸)R⁹ wherein        -   R⁸ is in each instance independently selected from H and            (C₁₋₆)alkyl; and        -   R⁹ is in each instance independently selected from R⁷,            —SO₂—R⁷, —C(═O)—R⁷, —C(═O)OR⁷ and —C(═O)N(R⁸)R⁷; wherein R⁷            and R⁸ are as defined above.

-   R²⁰-D: In another embodiment, R²⁰ is selected from:    -   b) —(C₁₋₃)alkylene-R⁷, —(C₁₋₃)alkylene-O—R⁷,        —(C₁₋₃)alkylene-S—R⁷ or —(C₁₋₃)alkylene-SO₂—R⁷;        -   wherein R⁷ is Het; wherein the Het is a 5- or 6-membered            heterocycle containing 1 to 4 heteroatoms, each            independently selected from N, O and S, or Het is a 9- or            10-membered heteropolycycle containing 1 to 4 heteroatoms,            each independently selected from N, O and S; wherein each N            heteroatom may, independently and where possible, exist in            an oxidized state such that it is further bonded to an            oxygen atom to form an N-oxide group and wherein each S            heteroatom may, independently and where possible, exist in            an oxidized state such that it is further bonded to one or            two oxygen atoms to form the groups SO or SO₂;        -   wherein the Het is optionally substituted with 1 to 3            substituents each independently selected from halo, cyano,            oxo, imino, —OH, —O—(C₁₋₆)alkyl, —O—(C₁₋₆)haloalkyl,            (C₃₋₇)cycloalkyl, —NH₂, —NH(C₁₋₄)alkyl, —NH(C₃₋₇)cycloalkyl,            —N((C₁₋₄)alkyl)(C₃₋₇)cycloalkyl, —N((C₁₋₄)alkyl)₂,            —NH—C(═O)(C₁₋₄)alkyl, (C₁₋₆)alkyl and Het, wherein the Het            is a 5- or 6-membered heterocycle containing 1 to 4            heteroatoms, each independently selected from N, O and S;            and    -   c) —(C₁₋₃)alkylene-N(R⁸)R⁹ wherein        -   R⁸ is in each instance independently selected from H,            (C₁₋₆)alkyl and (C₃₋₇)cycloalkyl; and        -   R⁹ is R⁷ wherein R⁷ is as defined above.

-   R²⁰-E: In another embodiment, R²⁰ is selected from:    -   b) —CH₂—R⁷, —CH₂CH₂—R⁷, —CH₂—O—R⁷, —CH₂—S—R⁷ or —CH₂—SO₂—R⁷;        -   wherein R⁷ is Het; wherein the Het is selected from:

-   -   -   wherein the Het is optionally substituted with 1 to 3            substituents each independently selected from halo, cyano,            oxo, imino, —OH, —O—(C₁₋₆)alkyl, —NH₂, —NH(C₁₋₄)alkyl,            —N((C₁₋₄)alkyl)₂, —NH—C(═O)(C₁₋₄)alkyl, (C₁₋₆)alkyl and

-   -   -    and

    -   c) —CH₂—N(R⁸)R⁹ wherein        -   R⁸ is in each instance independently selected from H and            (C₁₋₆)alkyl; and        -   R⁹ is R⁷ wherein R⁷ is as defined above.

Therefore, examples of embodiments of R² are set forth in the followingtable, wherein each substituent group is defined according to thedefinitions set forth above:

Embodiment Het R²⁰ R²-A Het-A R²⁰-A R²-B Het-B R²⁰-A R²-C Het-C R²⁰-AR²-D Het-D R²⁰-A R²-E Het-E R²⁰-A R²-F Het-E R²⁰-B R²-G Het-E R²⁰-C R²-HHet-E R²⁰-D R²-I Het-E R²⁰-E

-   R²-J: In another embodiment, R² is selected from:

-   -   or R² is a group of the formula:

-   -   wherein R²³ is selected from:

Any and each individual definition of R² as set out herein may becombined with any and each individual definition of X, R³, R⁵ and R⁶ asset out herein.

-   R³:-   R³-A: In one embodiment, R³ is selected from H, halo, (C₁₋₄)alkyl,    —O—(C₁₋₄)alkyl and —N((C₁₋₄)alkyl)₂.-   R³-B: In another embodiment, R³ is selected from H and halo.-   R³-C: In another embodiment, R³ is H or F.-   R³-D: In another embodiment, R³ is H.

Any and each individual definition of R³ as set out herein may becombined with any and each individual definition of X, R², R⁵ and R⁶ asset out herein.

-   R⁵:-   R⁵-A: In one embodiment, R⁵ is (C₁₋₆)alkyl.-   R⁵-B: In another embodiment, R⁵ is methyl or 1-methylethyl.-   R⁵-C: In another embodiment, R⁵ is 1-methylethyl.-   R⁵-D: In another embodiment, R⁵ is (C₁₋₄)alkyl substituted with Het,    —COOH or —C(═O)—N(R⁵¹)R⁵², wherein the Het is a 5- or 6-membered    heterocycle containing from 1 to 4 N heteroatoms or Het is a 9- or    10-membered bicyclic heteropolycycle containing from 1 to 4 N    heteroatoms;    -   and wherein R⁵¹ is H or (C₁₋₆)alkyl and R⁵² is selected from H,        (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, Het and Het-(C₁₋₃)alkyl-;        -   wherein the (C₁₋₆)alkyl is optionally substituted with 1 or            2 substituents each independently selected from            —O(C₁₋₆)alkyl and —N((C₁₋₆)alkyl)₂; and wherein the Het and            the Het portion of Het-(C₁₋₃)alkyl- are each independently a            5- or 6-membered heterocycle containing 1 to 3 heteroatoms            each independently selected from N, O and S, wherein the Het            and the Het-(C₁₋₃)alkyl- are each optionally substituted            with 1 to 3 substituents each independently selected from            halo, oxo, —OH, (C₁₋₆)alkyl, (C₁₋₆)haloalkyl,            —(C═O)(C₁₋₆)alkyl, —N((C₁₋₆)alkyl)₂ and —NH(C═O)(C₁₋₆)alkyl,            -   wherein the (C₁₋₆)alkyl is optionally substituted with                OH;    -   or R⁵¹ and R⁵², together with the N to which they are attached,        are linked to form a 4- to 7-membered heterocycle optionally        further containing 1 to 3 heteroatoms each independently        selected from N, O and S, wherein each S heteroatom may,        independently and where possible, exist in an oxidized state        such that it is further bonded to one or two oxygen atoms to        form the groups SO or SO₂;        -   wherein the heterocycle is optionally substituted with 1 to            3 substituents each independently selected from halo, oxo,            —OH, (C₁₋₆)alkyl, (C₁₋₆)haloalkyl, —(C═O)(C₁₋₆)alkyl,            —N((C₁₋₆)alkyl)₂ and —NH(C═O)(C₁₋₆)alkyl,            -   wherein the (C₁₋₆)alkyl is optionally substituted with                OH.-   R⁵-E: In another embodiment, R⁵ is (C₁₋₂)alkyl substituted with Het,    —COOH or —C(═O)—N(R⁵¹)R⁵², wherein the Het is selected from

-   -   and wherein R⁵¹ is H or (C₁₋₆)alkyl and R⁵² is selected from H,        (C₁₋₄)alkyl, (C₃₋₆)cycloalkyl, Het and Het-(C₁₋₃)alkyl-;        -   wherein the (C₁₋₆)alkyl is optionally substituted with 1 or            2 substituents each independently selected from            —O(C₁₋₄)alkyl and —N((C₁₋₄)alkyl)₂; and wherein the Het and            the Het portion of Het-(C₁₋₃)alkyl- are each independently            selected from:

-   -   -   wherein the Het and the Het-(C₁₋₃)alkyl- are each optionally            substituted with 1 to 3 substituents each independently            selected from halo, oxo, —OH, (C₁₋₆)alkyl, (C₁₋₆)haloalkyl,            —(C═O)(C₁₋₆)alkyl, —N((C₁₋₆)alkyl)₂ and —NH(C═O)(C₁₋₆)alkyl,            -   wherein the (C₁₋₆)alkyl is optionally substituted with                OH;

    -   or R⁵¹ and R⁵², together with the N to which they are attached,        are linked to form a heterocycle selected from:

-   -   -   wherein the heterocycle is optionally substituted with 1 to            3 substituents each independently selected from halo, oxo,            —OH, (C₁₋₆)alkyl, (C₁₋₆)haloalkyl, —(C═O)(C₁₋₆)alkyl,            —N((C₁₋₆)alkyl)₂ and —NH(C═O)(C₁₋₆)alkyl,            -   wherein the (C₁₋₆)alkyl is optionally substituted with                OH.

-   R⁵-F: In another embodiment, R⁵ is —CH₂—C(═O)—N(R⁵¹)R⁵²;    -   wherein R⁵¹ is H or (C₁₋₆)alkyl and R⁵² is selected from H,        (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, Het and Het-(C₁₋₃)alkyl-;        -   wherein the (C₁₋₆)alkyl is optionally substituted with 1 or            2 substituents each independently selected from            —O(C₁₋₆)alkyl and —N((C₁₋₆)alkyl)₂; and wherein the Het and            the Het portion of Het-(C₁₋₃)alkyl- are each independently a            5- or 6-membered heterocycle containing 1 to 3 heteroatoms            each independently selected from N, O and S, wherein the Het            and the Het-(C₁₋₃)alkyl- are each optionally substituted            with 1 to 3 substituents each independently selected from            halo, oxo, —OH, (C₁₋₆)alkyl, (C₁₋₆)haloalkyl,            —(C═O)(C₁₋₆)alkyl, —N((C₁₋₆)alkyl)₂ and —NH(C═O)(C₁₋₆)alkyl,            -   wherein the (C₁₋₆)alkyl is optionally substituted with                OH;    -   or R⁵¹ and R⁵², together with the N to which they are attached,        are linked to form a 5- or 6-membered heterocycle optionally        further containing 1 to 3 heteroatoms each independently        selected from N, O and S, wherein each S heteroatom may,        independently and where possible, exist in an oxidized state        such that it is further bonded to one or two oxygen atoms to        form the groups SO or SO₂;        -   wherein the heterocycle is optionally substituted with 1 to            3 substituents each independently selected from halo, oxo,            —OH, (C₁₋₆)alkyl, (C₁₋₆)haloalkyl, —(C═O)(C₁₋₆)alkyl,            —N((C₁₋₆)alkyl)₂ and —NH(C═O)(C₁₋₆)alkyl,            -   wherein the (C₁₋₆)alkyl is optionally substituted with                OH.

-   R⁵-G: In another embodiment, R⁵ is —CH₂—C(═O)—N(R⁵¹)R⁵², wherein R⁵¹    is H or (C₁₋₆)alkyl and R⁵² is H or (C₁₋₆)alkyl.

-   R⁵-H: In another embodiment, R⁵ is Het optionally substituted with 1    to 4 substituents each independently selected from (C₁₋₆)alkyl, —OH,    —COOH, —C(═O)—(C₁₋₆)alkyl, —C(═O)—O—(C₁₋₆)alkyl,    —C(═O)—NH—(C₁₋₆)alkyl, —C(═O)—N((C₁₋₆)alkyl)₂,    —C(═O)—NH(C₃₋₇)cycloalkyl, —C(═O)—N((C₁₋₄)alkyl)(C₃₋₇)cycloalkyl and    —SO₂(C₁₋₆)alkyl.

-   R⁵-I: In another embodiment, R⁵ is a 5- or 6-membered saturated    heterocycle containing 1 to 3 heteroatoms each independently    selected from O, N and S, the heterocycle being optionally    substituted with 1 to 4 substituents each independently selected    from (C₁₋₄)alkyl, —C(═O)—(C₁₋₄)alkyl, —C(═O)—O—(C₁₋₄)alkyl,    —C(═O)—NH—(C₁₋₄)alkyl, —C(═O)—N((C₁₋₄)alkyl)₂,    —C(═O)—NH(C₃₋₇)cycloalkyl, —C(═O)—N((C₁₋₄)alkyl)(C₃₋₇)cycloalkyl and    —SO₂(C₁₋₄)alkyl.

-   R⁵-J: In another embodiment, R⁵ is selected from H, methyl, ethyl,    propyl, 1-

Any and each individual definition of R⁵ as set out herein may becombined with any and each individual definition of X, R², R³ and R⁶ asset out herein.

-   R⁶:-   R⁶-A: In one embodiment, R⁶ is (C₃₋₇)cycloalkyl optionally    substituted with 1 to 5 substituents each independently selected    from halo, (C₁₋₆)alkyl, (C₁₋₆)haloalkyl, (C₃₋₇)cycloalkyl, —OH, —SH,    —O—(C₁₋₄)alkyl and —S—(C₁₋₄)alkyl.-   R⁶-B: In another embodiment, R⁶ is cyclohexyl optionally substituted    with 1 to 3 substituents each independently selected from —OH and    (C₁₋₄)alkyl.-   R⁶-C: In still another embodiment, R⁶ is selected from:

-   R⁶-D: In still another embodiment, R⁶ is

-   R⁶-E: In an alternative embodiment, R⁶ is aryl optionally    substituted with 1 to 5 substituents each independently selected    from halo, (C₁₋₆)alkyl, (C₁₋₆)haloalkyl, (C₃₋₇)cycloalkyl, —OH, —SH,    —O—(C₁₋₄)alkyl and —S—(C₁₋₄)alkyl;    -   provided that when R² is selected from:

-   -   X is O; R³ is H; and R⁵ is H;    -   then R⁶ is not

-   R⁶-F: In another alternative embodiment, R⁶ is phenyl optionally    substituted with 1 to 3 substituents each independently selected    from halo, (C₁₋₄)alkyl, (C₃₋₇)cycloalkyl and —S—(C₁₋₄)alkyl;    -   provided that when R² is selected from:

-   -   X is O; R³ is H; and R⁵ is H;    -   then R⁶ is not

-   R⁶-G: In yet another alternative embodiment, R⁶ is phenyl optionally    substituted with 1 to 3 substituents each independently selected    from F, Cl, Br, methyl, ethyl, cyclopropyl and —S—CH₃;    -   provided that when R² is selected from:

-   -   X is O; R³ is H; and R⁵ is H;    -   then R⁶ is not

-   R⁶-H: In still another embodiment, R⁶ is selected from:

-   -   provided that when R² is selected from:

-   -   X is O; R³ is H; and R⁵ is H;    -   then R⁵ is not

Any and each individual definition of R⁶ as set out herein may becombined with any and each individual definition of X, R², R³, and R⁵ asset out herein.

Examples of preferred subgeneric embodiments of the present inventionare set forth in the following table, wherein each substituent group ofeach embodiment is defined according to the definitions set forth above:

Embodiment X R² R³ R⁵ R⁶ E-1 X-A R²-A R³-B R⁵-A R⁶-A E-2 X-B R²-A R³-BR⁵-A R⁶-A E-3 X-A R²-A R³-B R⁵-D R⁶-A E-4 X-B R²-A R³-B R⁵-D R⁶-A E-5X-A R²-A R³-B R⁵-H R⁶-A E-6 X-B R²-A R³-B R⁵-H R⁶-A E-7 X-A R²-A R³-BR⁵-A R⁶-E E-8 X-B R²-A R³-B R⁵-A R⁶-E E-9 X-A R²-A R³-B R⁵-D R⁶-E E-10X-B R²-A R³-B R⁵-D R⁶-E E-11 X-A R²-A R³-B R⁵-H R⁶-E E-12 X-B R²-A R³-BR⁵-H R⁶-E E-13 X-A R²-A R³-D R⁵-A R⁶-A E-14 X-B R²-A R³-D R⁵-A R⁶-A E-15X-A R²-A R³-D R⁵-D R⁶-A E-16 X-B R²-A R³-D R⁵-D R⁶-A E-17 X-A R²-A R³-DR⁵-H R⁶-A E-18 X-B R²-A R³-D R⁵-H R⁶-A E-19 X-A R²-A R³-D R⁵-A R⁶-E E-20X-B R²-A R³-D R⁵-A R⁶-E E-21 X-A R²-A R³-D R⁵-D R⁶-E E-22 X-B R²-A R³-DR⁵-D R⁶-E E-23 X-A R²-A R³-D R⁵-H R⁶-E E-24 X-B R²-A R³-D R⁵-H R⁶-E E-25X-A R²-D R³-D R⁵-B R⁶-B E-26 X-A R²-D R³-D R⁵-F R⁶-B E-27 X-A R²-D R³-DR⁵-I R⁶-B E-28 X-A R²-D R³-D R⁵-B R⁶-D E-29 X-A R²-D R³-D R⁵-F R⁶-D E-30X-A R²-D R³-D R⁵-I R⁶-D E-31 X-A R²-D R³-D R⁵-B R⁶-F E-32 X-A R²-D R³-DR⁵-F R⁶-F E-33 X-A R²-D R³-D R⁵-I R⁶-F E-34 X-A R²-F R³-D R⁵-B R⁶-B E-35X-A R²-F R³-D R⁵-F R⁶-B E-36 X-A R²-F R³-D R⁵I R⁶-B E-37 X-A R²-F R³-DR⁵-B R⁶-D E-38 X-A R²-F R³-D R⁵-F R⁶-D E-39 X-A R²-F R³-D R⁵-I R⁶-D E-40X-A R²-F R³-D R⁵-B R⁶-F E-41 X-A R²-F R³-D R⁵-F R⁶-F E-42 X-A R²-F R³-DR⁵-I R⁶-F E-43 X-A R²-H R³-D R⁵-B R⁶-B E-44 X-A R²-H R³-D R⁵-F R⁶-B E-45X-A R²-H R³-D R⁵-I R⁶-B E-46 X-A R²-H R³-D R⁵-B R⁶-D E-47 X-A R²-H R³-DR⁵-F R⁶-D E-48 X-A R²-H R³-D R⁵-I R⁶-D E-49 X-A R²-H R³-D R⁵-B R⁶-F E-50X-A R²-H R³-D R⁵-F R⁶-F E-51 X-A R²-H R³-D R⁵-I R⁶-F

Examples of most preferred compounds according to this invention areeach single compound listed in the following Tables 1 and 2.

In general, all tautomeric and isomeric forms and mixtures thereof, forexample, individual geometric isomers, stereoisomers, enantiomers,diastereomers, racemates, racemic or non-racemic mixtures ofstereoisomers, mixtures of diastereomers, or mixtures of any of theforegoing forms of a chemical structure or compound is intended, unlessthe specific stereochemistry or isomeric form is specifically indicatedin the compound name or structure.

It is well-known in the art that the biological and pharmacologicalactivity of a compound is sensitive to the stereochemistry of thecompound. Thus, for example, enantiomers often exhibit strikinglydifferent biological activity including differences in pharmacokineticproperties, including metabolism, protein binding, and the like, andpharmacological properties, including the type of activity displayed,the degree of activity, toxicity, and the like. Thus, one skilled in theart will appreciate that one enantiomer may be more active or mayexhibit beneficial effects when enriched relative to the otherenantiomer or when separated from the other enantiomer. Additionally,one skilled in the art would know how to separate, enrich, orselectively prepare the enantiomers of the compounds of the presentinvention from this disclosure and the knowledge in the art.

Preparation of pure stereoisomers, e.g. enantiomers and diastereomers,or mixtures of desired enantiomeric excess (ee) or enantiomeric purity,are accomplished by one or more of the many methods of (a) separation orresolution of enantiomers, or (b) enantioselective synthesis known tothose of skill in the art, or a combination thereof. These resolutionmethods generally rely on chiral recognition and include, for example,chromatography using chiral stationary phases, enantioselectivehost-guest complexation, resolution or synthesis using chiralauxiliaries, enantioselective synthesis, enzymatic and nonenzymatickinetic resolution, or spontaneous enantioselective crystallization.Such methods are disclosed generally in Chiral Separation Techniques: APractical Approach (2nd Ed.), G. Subramanian (ed.), Wiley-VCH, 2000; T.E. Beesley and R. P. W. Scott, Chiral Chromatography, John Wiley & Sons,1999; and Satinder Ahuja, Chiral Separations by Chromatography, Am.Chem. Soc., 2000, herein incorporated by reference. Furthermore, thereare equally well-known methods for the quantitation of enantiomericexcess or purity, for example, GC, HPLC, CE, or NMR, and assignment ofabsolute configuration and conformation, for example, CD ORD, X-raycrystallography, or NMR.

The compounds according to the present invention are inhibitors of thehepatitis C virus NS5B RNA-dependent RNA polymerase and thus may be usedto inhibit replication of hepatitis C viral RNA.

A compound according to the present invention may also be used as alaboratory reagent or a research reagent. For example, a compound of thepresent invention may be used as positive control to validate assays,including but not limited to surrogate cell-based assays and in vitro orin vivo viral replication assays.

Compounds according to the present invention may also be used as probesto study the hepatitis C virus NS5B polymerase, including but notlimited to the mechanism of action of the polymerase, conformationalchanges undergone by the polymerase under various conditions andinteractions with entities which bind to or otherwise interact with thepolymerase.

Compounds of the invention used as probes may be labelled with a labelwhich allows recognition either directly or indirectly of the compoundsuch that it can be detected, measured and quantified. Labelscontemplated for use with the compounds of the invention include, butare not limited to, fluorescent labels, chemiluminescent labels,calorimetric labels, enzymatic markers, radioactive isotopes, affinitytags and photoreactive groups.

Compounds of the invention used as probes may also be labelled with anaffinity tag whose strong affinity for a receptor can be used to extractfrom a solution the entity to which the ligand is attached. Affinitytags include but are not limited to biotin or a derivative thereof, ahistidine polypeptide, a polyarginine, an amylose sugar moiety or adefined epitope recognizable by a specific antibody.

Furthermore, compounds of the invention used as probes may be labelledwith a photoreactive group which is transformed, upon activation bylight, from an inert group to a reactive species, such as a freeradical. Photoreactive groups include but are not limited tophotoaffinity labels such as benzophenone and azide groups.

Furthermore, a compound according to the present invention may be usedto treat or prevent viral contamination of materials and thereforereduce the risk of viral infection of laboratory or medical personnel orpatients who come in contact with such materials (e.g. blood, tissue,surgical instruments and garments, laboratory instruments and garments,and blood collection apparatuses and materials).

Pharmaceutical Composition

Compounds of the present invention may be administered to a mammal inneed of treatment for hepatitis C viral infection as a pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundaccording to the invention or a pharmaceutically acceptable salt orester thereof; and one or more conventional non-toxicpharmaceutically-acceptable carriers, adjuvants or vehicles. Thespecific formulation of the composition is determined by the solubilityand chemical nature of the compound, the chosen route of administrationand standard pharmaceutical practice. The pharmaceutical compositionaccording to the present invention may be administered orally orsystemically.

For oral administration, the compound, or a pharmaceutically acceptablesalt or ester thereof, can be formulated in any orally acceptable dosageform including but not limited to aqueous suspensions and solutions,capsules or tablets. For systemic administration, including but notlimited to administration by subcutaneous, intracutaneous, intravenous,intramuscular, intra-articular, intrasynovial, intrasternal,intrathecal, and intralesional injection or infusion techniques, it ispreferred to use a solution of the compound, or a pharmaceuticallyacceptable salt or ester thereof, in a pharmaceutically acceptablesterile aqueous vehicle.

Pharmaceutically acceptable carriers, adjuvants, vehicles, excipientsand additives as well as methods of formulating pharmaceuticalcompositions for various modes of administration are well-known to thoseof skill in the art and are described in pharmaceutical texts such asRemington: The Science and Practice of Pharmacy, 21 st Edition,Lippincott Williams & Wilkins, 2005; and L. V. Allen, N. G. Popovish andH. C. Ansel, Pharmaceutical Dosage Forms and Drug Delivery Systems, 8thed., Lippincott Williams & Wilkins, 2004, herein incorporated byreference.

The dosage administered will vary depending upon known factors,including but not limited to the activity and pharmacodynamiccharacteristics of the specific compound employed and its mode, time androute of administration; the age, diet, gender, body weight and generalhealth status of the recipient; the nature and extent of the symptoms;the severity and course of the infection; the kind of concurrenttreatment; the frequency of treatment; the effect desired; and thejudgment of the treating physician. In general, the compound is mostdesirably administered at a dosage level that will generally affordantivirally effective results without causing any harmful or deleteriousside effects.

A daily dosage of active ingredient can be expected to be about 0.01 toabout 200 milligrams per kilogram of body weight, with the preferreddose being about 0.1 to about 50 mg/kg. Typically, the pharmaceuticalcomposition of this invention will be administered from about 1 to about5 times per day or alternatively, as a continuous infusion. Suchadministration can be used as a chronic or acute therapy. The amount ofactive ingredient that may be combined with the carrier materials toproduce a single dosage form will vary depending upon the host treatedand the particular mode of administration. A typical preparation willcontain from about 5% to about 95% active compound (w/w). Preferably,such preparations contain from about 20% to about 80% active compound.

Combination Therapy

Combination therapy is contemplated wherein a compound according to theinvention, or a pharmaceutically acceptable salt or ester thereof, isco-administered with at least one additional antiviral agent. Theadditional agents may be combined with compounds of this invention tocreate a single dosage form. Alternatively these additional agents maybe separately administered, concurrently or sequentially, as part of amultiple dosage form.

When the pharmaceutical composition of this invention comprises acombination of a compound according to the invention, or apharmaceutically acceptable salt or ester thereof, and one or moreadditional antiviral agent, both the compound and the additional agentshould be present at dosage levels of between about 10 to 100%, and morepreferably between about 10 and 80% of the dosage normally administeredin a monotherapy regimen. In the case of a synergistic interactionbetween the compound of the invention and the additional antiviral agentor agents, the dosage of any or all of the active agents in thecombination may be reduced compared to the dosage normally administeredin a monotherapy regimen.

Antiviral agents contemplated for use in such combination therapyinclude agents (compounds or biologicals) that are effective to inhibitthe formation and/or replication of a virus in a mammal, including butnot limited to agents that interfere with either host or viralmechanisms necessary for the formation and/or replication of a virus ina mammal. Such agents can be selected from another anti-HCV agent; anHIV inhibitor; an HAV inhibitor; and an HBV inhibitor.

Other anti-HCV agents include those agents that are effective fordiminishing or preventing the progression of hepatitis C relatedsymptoms or disease. Such agents include but are not limited toimmunomodulatory agents, inhibitors of HCV NS3 protease, otherinhibitors of HCV polymerase, inhibitors of another target in the HCVlife cycle and other anti-HCV agents, including but not limited toribavirin, amantadine, levovirin and viramidine.

Immunomodulatory agents include those agents (compounds or biologicals)that are effective to enhance or potentiate the immune system responsein a mammal. Immunomodulatory agents include, but are not limited to,inosine monophosphate dehydrogenase inhibitors such as VX-497(merimepodib, Vertex Pharmaceuticals), class I interferons, class IIinterferons, consensus interferons, asialo-interferons pegylatedinterferons and conjugated interferons, including but not limited tointerferons conjugated with other proteins including but not limited tohuman albumin. Class I interferons are a group of interferons that allbind to receptor type I, including both naturally and syntheticallyproduced class I interferons, while class II interferons all bind toreceptor type II. Examples of class I interferons include, but are notlimited to, α-, β-, δ-, ω-, and τ-interferons, while examples of classII interferons include, but are not limited to, γ-interferons.

Inhibitors of HCV NS3 protease include agents (compounds or biologicals)that are effective to inhibit the function of HCV NS3 protease in amammal. Inhibitors of HCV NS3 protease include, but are not limited to,those compounds described in WO 99/07733, WO 99/07734, WO 00/09558, WO00/09543, WO 00/59929, WO 03/064416, WO 03/064455, WO 03/064456, WO2004/030670, WO 2004/037855, WO 2004/039833, WO 2004/101602, WO2004/101605, WO 2004/103996, WO 2005/028501, WO 2005/070955, WO2006/000085, WO 2006/007700, WO 2006/007708 (all by BoehringerIngelheim), WO 02/060926, WO 03/053349, WO 03/099274, WO 03/099316, WO2004/032827, WO 2004/043339, WO 2004/094452, WO 2005/046712, WO2005/051410, WO 2005/054430 (all by BMS), WO 2004/072243, WO2004/093798, WO 2004/113365, WO 2005/010029 (all by Enanta), WO2005/037214 (Intermune), WO 01/77113, WO 01/81325, WO 02/08187, WO02/08198, WO 02/08244, WO 02/08256, WO 02/48172, WO 03/062228, WO03/062265, WO 2005/021584, WO 2005/030796, WO 2005/058821, WO2005/051980, WO 2005/085197, WO 2005/085242, WO 2005/085275, WO2005/087721, WO 2005/087725, WO 2005/087730, WO 2005/087731, WO2005/107745 and WO 2005/113581 (all by Schering); and the candidatesVX-950, ITMN-191 and SCH-503034.

Inhibitors of HCV polymerase include agents (compounds or biologicals)that are effective to inhibit the function of an HCV polymerase. Suchinhibitors include, but are not limited to, non-nucleoside andnucleoside inhibitors of HCV NS5B polymerase. Examples of inhibitors ofHCV polymerase include but are not limited to those compounds describedin: WO 02/04425, WO 03/007945, WO 03/010140, WO 03/010141, WO2004/064925, WO 2004/065367, WO 2005/080388, WO 2006/007693 (all byBoehringer Ingelheim), WO 01/47883 (Japan Tobacco), WO 03/000254 (JapanTobacco), WO 03/026587 (BMS), WO 03/101993 (Neogenesis), WO 2004/087714(IRBM), WO 2005/012288 (Genelabs), WO 2005/014543 (Japan Tobacco), WO2005/049622 (Japan Tobacco), and WO 2005/121132 (Shionogi), and thecandidates XTL-2125, HCV 796, R-1626, R-7128, NM 283, VCH-759, GSK625433and PF868554. Inhibitors of another target in the HCV life cycle includeagents (compounds or biologicals) that are effective to inhibit theformation and/or replication of HCV other than by inhibiting thefunction of the HCV NS3 protease or HCV polymerase. Such agents mayinterfere with either host or HCV viral mechanisms necessary for theformation and/or replication of HCV. Inhibitors of another target in theHCV life cycle include, but are not limited to, entry inhibitors, agentsthat inhibit a target selected from a helicase, a NS2/3 protease and aninternal ribosome entry site (IRES) and agents that interfere with thefunction of other viral targets including but not limited to an NS5Aprotein and an NS4B protein.

It can occur that a patient may be co-infected with hepatitis C virusand one or more other viruses, including but not limited to humanimmunodeficiency virus (HIV), hepatitis A virus (HAV) and hepatitis Bvirus (HBV). Thus also contemplated is combination therapy to treat suchco-infections by co-administering a compound according to the presentinvention with at least one of an HIV inhibitor, an HAV inhibitor and anHBV inhibitor.

HIV inhibitors include agents (compounds or biologicals) that areeffective to inhibit the formation and/or replication of HIV. Thisincludes but is not limited to agents that interfere with either host orviral mechanisms necessary for the formation and/or replication of HIVin a mammal. HIV inhibitors include, but are not limited to:

-   -   NRTIs (nucleoside or nucleotide reverse transcriptase        inhibitors; including but not limited to zidovudine, didanosine,        zalcitabine, stavudine, lamivudine, emtricitabine, abacavir, and        tenofovir);    -   NNRTIs (non-nucleoside reverse transcriptase inhibitors;        including but not limited to nevirapine, delavirdine, efavirenz,        etravirine, rilpivirine and BILR 355);    -   protease inhibitors (including but not limited to ritonavir,        tipranavir, saquinavir, nelfinavir, indinavir, amprenavir,        fosamprenavir, atazanavir, lopinavir, darunavir and brecanavir);    -   entry inhibitors including but not limited to        -   CCR5 antagonists (including but not limited to maraviroc            (UK-427,857) and TAK-652),        -   CXCR4 antagonists (including but not limited to AMD-11070),        -   fusion inhibitors (including but not limited to enfuvirtide            (T-20)) and        -   others (including but not limited to BMS-488043);    -   integrase inhibitors (including but not limited to MK-0518,        c-1605, BMS-538158 and GS 9137);    -   TAT inhibitors;    -   maturation inhibitors (including but not limited to bevirimat        (PA-457)); and    -   immunomodulating agents (including but not limited to        levamisole).

HAV inhibitors include agents (compounds or biologicals) that areeffective to inhibit the formation and/or replication of HAV. Thisincludes but is not limited to agents that interfere with either host orviral mechanisms necessary for the formation and/or replication of HAVin a mammal. HAV inhibitors include but are not limited to Hepatitis Avaccines.

HBV inhibitors include agents (compounds or biologicals) that areeffective to inhibit the formation and/or replication of HBV in amammal. This includes but is not limited to agents that interfere witheither host or viral mechanisms necessary for the formation and/orreplication of HBV in a mammal. HBV inhibitors include, but are notlimited to, agents that inhibit the HBV viral DNA polymerase and HBVvaccines.

Therefore, according to one embodiment, the pharmaceutical compositionof this invention additionally comprises a therapeutically effectiveamount of one or more antiviral agents.

A further embodiment provides the pharmaceutical composition of thisinvention wherein the one or more antiviral agent comprises at least oneother anti-HCV agent.

According to a more specific embodiment of the pharmaceuticalcomposition of this invention, the at least one other anti-HCV agentcomprises at least one immunomodulatory agent.

According to another more specific embodiment of the pharmaceuticalcomposition of this invention, the at least one other anti-HCV agentcomprises at least one other inhibitor of HCV polymerase.

According to yet another more specific embodiment of the pharmaceuticalcomposition of this invention, the at least one other anti-HCV agentcomprises at least one inhibitor of HCV NS3 protease.

According to still another more specific embodiment of thepharmaceutical composition of this invention, the at least one otheranti-HCV agent comprises at least one inhibitor of another target in theHCV life cycle.

All of the documents cited herein are incorporated in to the inventionas a reference, as if each of them is individually incorporated.Further, it would be appreciated that, in the above teaching ofinvention, the skilled in the art could make certain changes ormodifications to the invention, and these equivalents would still bewithin the scope of the invention defined by the appended claims of theapplication.

Methodology and Synthesis

The synthesis of compounds of formula (I) according to this invention isconveniently accomplished following the general procedure outlined inSchemes 1 and 2 below wherein R², X, R³, R⁵ and R⁶ are as definedherein. Other procedures by which compounds of the invention may beprepared are well known in the art or are set forth in the examplesbelow.

Intermediates of formula (II) wherein R^(3a) is R³ as defined herein oris a precursor group transformable to R³ as defined herein, R is anester protecting group, such as methyl or ethyl, and LG is a leavinggroup such as F or Cl, are commercially available or may be prepared byprocedures well known in the art or as set forth in the examples below.It will be apparent to one skilled in the art that when the group R^(3a)is a precursor group, it may be transformed to R³ as defined herein atany chemically convenient intermediate stage in the scheme prior toformation of the compounds of formula (I), by procedures well known inthe art or as set forth in the examples below.

Coupling of intermediates (II) with reactants of the formula R²X—H,wherein R² and X are as defined herein, using reaction conditions wellknown in the art or as set forth in the examples below, providesintermediates of formula (III). Such reaction conditions include but arenot limited to S_(N)Ar reaction conditions and Ullman couplingconditions. One skilled in the art will appreciate that R² groups of thecompounds according to the invention differ in their substitutionpatterns and that it is contemplated that one R² group may betransformed to another R² group by procedures well known in the art oras set forth in the examples below, at any chemically convenientintermediate stage in the scheme.

The nitro group of intermediates (III) is reduced to an amino groupunder well-known conditions to provide intermediates of formula (IV), ortheir salts with acids such as hydrochloric acid. The R⁵ group may beadded to the amino group of intermediates of formula (IV) by anysuitable reaction known to the skilled in the art, including but notlimited to alkylation and reductive amination, to provide intermediatesof formula (V). The reductive amination reaction is conveniently carriedout by allowing the intermediate of formula (IV) to react with anappropriately substituted aldehyde or ketone or suitable derivativethereof, followed by treatment with sodium triacetoxyborohydride,according to Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.;Maryanoff, C. A.; Shah, R. D. J. Org. Chem. 1996, 61, 3849. Suitablederivatives of aldehydes and ketones are well known in the art andinclude, but are not limited to, enol ethers and the like. Thealdehydes, ketones, or suitable derivatives thereof are commerciallyavailable or obtainable by procedures well known in the art or as setforth in the examples below. Intermediates (V) are acylated withappropriate acylating agents, which are commercially available orobtainable by procedures well known in the art or as set forth in theexamples below. The ester protecting group R is then hydrolysed, byprocedures well known in the art or as set forth in the examples below,to provide compounds of formula (I).

Alternatively, the amino group of intermediates of formula (IV) may beacylated as previously described to provide intermediates of formula(VI). Alkylation of the amide nitrogen atom of intermediates of formula(VI), by procedures well known in the art or as set forth in theexamples below, followed by hydrolysis of the ester protecting group aspreviously described, provides compounds of formula (I).

One skilled in the art will appreciate that R⁵ and R⁶ groups of thecompounds according to the invention differ in their substitutionpatterns and that it is contemplated that one R⁵ group may betransformed to another R⁵ group, or that one R⁶ group may be transformedto another R⁶ group, by procedures well known in the art or as set forthin the examples below, at any chemically convenient intermediate stagein the scheme.

Alternatively, the preparation of compounds of formula (I) may beaccomplished by the procedure outlined in Scheme 2 below, wherein R², X,R³, R⁵ and R⁶ are as defined herein, R is an ester protecting group suchas methyl or ethyl and PG is a suitable protecting group for the XHfunctionality, well known to one skilled in the art, including but notlimited to a benzyl group.

Intermediates of formula VII are commercially available or may beprepared by procedures well known in the art or as set forth in theexamples below. Reduction of the nitro group to the amino group andintroduction of the R⁵ and —C(═O)R⁶ groups is achieved as describedabove to give intermediates of formula (XI). The intermediates offormula (XI) are transformed to compounds of formula (I) by deprotectingthe XH group by procedures well known in the art or as set forth in theexamples below and coupling the resulting free phenol or thiol to areactant of formula R²-LG wherein LG is a leaving group such as F or Cl,using procedures well known in the art or as set forth in the examplesbelow. Such procedures include but are not limited to S_(N)Ar reactionsand Ullman coupling reactions. Finally, the ester is deprotected byhydrolysis as previously described.

EXAMPLES

Other features of the present invention will become apparent from thefollowing non-limiting examples which illustrate, by way of example, theprinciples of the invention. As is well known to a person skilled in theart, reactions are performed in an inert atmosphere (including but notlimited to nitrogen or argon) where necessary to protect reactioncomponents from air or moisture. Temperatures are given in degreesCelsius (° C.). Solution percentages and ratios express a volume tovolume relationship, unless stated otherwise. Flash chromatography iscarried out on silica gel (SiO₂) according to the procedure of W. C.Still et al., J. Org. Chem., (1978), 43, 2923. Mass spectral analysesare recorded using electrospray mass spectrometry. Analytical HPLC iscarried out under standard conditions using a Combiscreen™ ODS-AQ C18reverse phase column, YMC, 50×4.6 mm i.d., 5 μM, 120 Å at 220 nM,elution with a linear gradient as described in the following table(Solvent A is 0.06% TFA in H₂O; solvent B is 0.06% TFA in CH₃CN):

Time (min) Flow (mL/min) Solvent A (%) Solvent B (%) 0 3.0 95 5 0.5 3.095 5 6.0 3.0 50 50 10.5 3.5 0 100

Abbreviations or symbols used herein include:

-   Ac: acetyl;-   AcCl: acetyl chloride;-   AcOH: acetic acid;-   Ac₂O: acetic anhydride;-   BINAP: 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl;-   Bn: benzyl (phenylmethyl);-   BnBr: benzyl bromide;-   BOC or Boc: tert-butyloxycarbonyl;-   Bu: butyl;-   n-BuOAc: n-butyl acetate-   DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene;-   DCE: dichloroethane;-   DCM: dichloromethane;-   DIEA: diisopropylethylamine;-   DMAP: 4-dimethylaminopyridine;-   DME: dimethoxyethane;-   DMF: N,N-dimethylformamide;-   DMSO: dimethylsulfoxide;-   EC₅₀: 50% effective concentration;-   EEDQ: 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline;-   eq.: molar equivalent;-   Et: ethyl;-   Et₃N: triethylamine;-   Et₂O: diethyl ether;-   EtOAc: ethyl acetate;-   EtOH: ethanol;-   HPLC: high performance liquid chromatography;-   IC₅₀: 50% inhibitory concentration;-   ^(i)Pr or i-Pr: 1-methylethyl (iso-propyl);-   Me: methyl;-   MeCN: acetonitrile;-   MeI: iodomethane;-   MeOH: methanol;-   MS: mass spectrometry (MALDI-TOF: Matrix Assisted Laser Desorption    Ionization-Time of Flight, FAB: Fast Atom Bombardment);-   NIS: N-iodosuccinamide;-   NMP: N-methylpyrrolidone;-   NMR: nuclear magnetic resonance spectroscopy;-   Ph: phenyl;-   PG: protecting group;-   Pr: propyl;-   RT: room temperature (approximately 18° C. to 25° C.);-   TBTU: O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium    tetrafluoroborate;-   tert-butyl or t-butyl: 1,1-dimethylethyl;-   TFA: trifluoroacetic acid;-   THF: tetrahydrofuran;-   TLC: thin layer chromatography.

Example 1A Preparation of Intermediate 1a9

Step 1:

To a mixture of 5-hydroxy-2-nitrobenzoic acid 1a1 (50 g, 0.273 mol) inMeOH (500 mL), is added SOCl₂ (40 mL, 65.2 g, 0.55 mol) dropwise overabout 30 minutes and the mixture is heated at reflux for 2 hours. ExcessSOCl₂ (20 mL, 32.6 g, 0.27 mol) is carefully added and heating at refluxis continued overnight. Further SOCl₂ (20 mL, 32.6 g, 0.27 mol) is addedand heating at reflux is continued for 1 hour. The reaction mixture iscooled to room temperature and concentrated under reduced pressure. Theresidue is diluted with EtOAc (600 mL), washed with saturated aqueousNaHCO₃ and brine, dried over MgSO₄, filtered and concentrated todryness. The methyl ester 1a2 is recovered as a solid from CH₂Cl₂ andhexane.

Step 2:

A mixture of compound 1a2 (51.2 g, 0.26 mol), anhydrous K₂CO₃ (150 g,1.09 mol) and PhCH₂Br (39 mL, 56 g, 0.33 mol) in acetone (500 mL) isstirred overnight at room temperature. The mixture is filtered and thefiltrate is concentrated, diluted with EtOAc (1.5 L), washed with waterand brine, dried over MgSO₄, filtered and concentrated to dryness.Compound 1a3 is recovered from EtOAc and hexane.

Step 3:

To a stirred mixture of compound 1a3 (68.4 g, 0.24 mol) in ethanol (1.2L) is added Fe powder (150 g, 2.7 mol) followed by AcOH (65 mL). Themixture is heated under reflux for 4 hours, then further Fe powder (75g, 1.3 mol) and AcOH (30 mL) are added and heating at reflux iscontinued for 1.5 hours. The mixture is filtered and the solid andfiltrate are treated separately.

The solid is mixed with saturated aqueous NaHCO₃ and EtOAc, and solidNaHCO₃ is added until a basic pH is attained. The mixture is filteredthrough Celite™ and rinsed with EtOAc. The aqueous layer is extractedtwice with EtOAc (2×1 L) and the organic layers are combined.

The filtrate is concentrated under reduced pressure, the residue isdiluted with EtOAc (1 L) and saturated aqueous NaHCO₃ is added. SolidNaHCO₃ is added to the mixture until the pH is basic. The mixture isfiltered through Celite™ and rinsed with EtOAc.

The organic phases obtained from treatment of the solid and filtrateportions above are combined, then washed with brine, dried over MgSO₄and concentrated to dryness and the residue is recovered from CH₂Cl₂ andhexane. To a stirred mixture of the recovered residue (46.7 g, 0.18 mol)in Et₂O (400 mL) is added 2M HCl in Et₂O (180 mL, 0.38 mol). The mixtureis stirred at room temperature for 2 hours and compound 1a4 is collectedby filtration.

Step 4:

The procedure used is adapted from: Abdel-Magid, A. F.; Carson, K. G.;Harris, B. D.; Maryanoff, C. A.; Shah, R. D. J. Org. Chem. 1996, 61,3849. To a mixture of compound 1a4 (30 g, 0.1 mol) and CH₂Cl₂ (600 mL)is added 2-methoxypropene (36 mL, 27 g, 0.38 mol), followed byNaBH(OAc)₃ (43.2 g, 0.2 mol). The mixture is stirred at RT for 7 hours,diluted with EtOAc, washed with saturated aqueous NaHCO₃ and brine,dried over MgSO₄, filtered and concentrated to dryness. Compound 1a5 isrecovered from EtOAc and hexane.

Step 5:

To a mixture of compound 1a6 (43.4 g, 305 mmol) and anhydrous CH₂Cl₂(400 mL) under Ar atmosphere at room temperature is added (COCl)₂ (53.2mL, 610 mmol) in CH₂Cl₂ (305 mL) dropwise over 1 hour at roomtemperature. The mixture is stirred for 1 hour at room temperature andanhydrous DMF (1 mL) is added dropwise. The mixture is stirred overnightat RT and concentrated under reduced pressure. The residue is dilutedwith pentane and filtered. The filtrate is twice concentrated underreduced pressure, diluted with pentane and filtered, then concentratedunder reduced pressure to provide acid chloride 1a7.

Step 6:

To a mixture of compound 1a5 (99.6 g, 0.32 mol) in anhydrous pyridine(1.5 L) is added compound 1a7 (100 mL, 100 g, 0.62 mol) and DMAP (3.8 g,0.03 mol). The mixture is stirred at 60° C. overnight and concentratedunder reduced pressure. The residue is diluted with EtOAc (3 L), washedwith 2M HCl aqueous solution (4×1 L), saturated aqueous NaHCO₃ (6×500mL) and brine, dried over MgSO₄, filtered and concentrated to dryness togive compound 1a8.

Step 7:

A mixture of compound 1a8 (130 g, 0.3 mol), MeOH (0.6 L) and EtOAc (1.5L) is carefully added to 10% Pd/C (15 g) under Ar. Argon is bubbledthrough the mixture for 10 minutes with stirring then H₂ is bubbled intothe mixture and stirring is continued at room temperature for 8 hours.The mixture is filtered through Celite™ and the filtrate is concentratedunder reduced pressure. Compound 1a9 is collected from Hexanes.

Example 1B Preparation of Intermediate 1b3

Step 1:

To a mixture of compound 1a4 (Example 1A) (2.0 g, 6.8 mmol) in anhydrouspyridine (35 mL) is added compound 1a7 (Example 1A) (1.65 mL, 10.2 mmol)and DMAP (82 mg, 0.67 mmol). The mixture is stirred at 50° C. for 1 hourand concentrated under reduced pressure. The residue is diluted withEtOAc (300 mL), washed with 2M HCl aqueous solution (5×200 mL),saturated aqueous NaHCO₃ solution (6×200 mL) and brine (200 mL), driedover MgSO₄, filtered and concentrated. Compound 1b1 is recovered fromDCM/Hexanes.

Step 2:

To a mixture of compound 1b1 (2.0 g, 5.24 mmol) and anhydrous DMF (30mL) cooled in an ice-water bath is added NaH (60%, 0.25 g, 10.5 mmol)and the mixture is stirred for 40 minutes. CH₃I (0.9 mL, 14.5 mmol, 2.8eq) is added and the mixture is allowed to stir at room temperatureovernight. The mixture is diluted with EtOAc (600 mL), washed withsaturated aqueous NH₄Cl (3×300 mL), saturated aqueous NaHCO₃ (300 mL)and brine (300 mL), dried over MgSO₄, filtered and concentrated. Thecrude product is purified by ISCO CombiFlash column (SiO₂, Hexane/EtOAc:10/0 to 5/5) to afford compound 1b2.

Step 3:

A mixture of compound 1b2 (2.07 g, 5.24. mmol) in anhydrous MeOH (33 mL)and anhydrous EtOAc (83 mL) is carefully added to Pd/C (10%, 0.23 g)under Ar atmosphere. Ar is bubbled through the mixture for 2 minutes andH₂ is then bubbled through the mixture with stirring at room temperaturefor 2.5 hours. The mixture is filtered through Celite™ and the filtrateis concentrated. Solid phenol 1b3 is obtained from adiethylether/hexanes mixture (1/9, 100 mL).

Intermediate 1b3 can be converted to compounds of formula (I) using themethods of the following examples.

Example 2A Preparation of Compound 1001, Table 1

Phenol 1a9 (Example 1A) (20 mg, 0.06 mmol) is combined with4-hydroxytetrahydropyran (0.08 mmol) and triphenylphosphine (20 mg, 0.08mmol) in THF (1 mL). Diisopropylazodicarboxylate (0.02 mL, 0.10 mmol) isadded and the mixture is allowed to stir overnight at ambienttemperature. Aqueous NaOH (10N, 0.06 mL, 0.6 mmol), water (0.06 mL) andmethanol (0.4 mL) are added and the mixture is warmed to 50° C. andallowed to stir for 2.5 hours. Purification by preparative HPLC affordscompound 1001 (Table 1).

Example 2B Preparation of Compound 1003, Table 1

Phenol 1a9 (Example 1A) (20 mg, 0.06 mmol) is combined with3-trifluoromethyl-4-chloropyridine (16 mg, 0.07 mmol) and K₂CO₃ (31 mg,0.22 mmol) in DMSO (0.5 mL). The mixture is heated to 100° C. andallowed to stir for 24 hours. Aqueous NaOH (5N, 0.12 mL, 0.6 mmol) isadded and the mixture is warmed to 55° C. and allowed to stir for 1hour. The mixture is acidified with AcOH and purified by preparativeHPLC to afford compound 1003 (Table 1).

Example 2C Preparation of Compound 1031, Table 1

A mixture of phenol 1a9 (Example 1A) (60 mg, 0.18 mmol),3-thiopheneboronic acid (46 mg, 0.36 mmol), Cu(OAc)₂ (33 mg, 0.18 mmol),Et₃N (0.13 mL, 0.90 mmol) and 4 Å molecular sieves (50 mg) in DCM isstirred for 20 h open to the atmosphere. The mixture is diluted withEtOAc and washed with aqueous 0.2 N HCl, saturated aqueous NaHCO₃ andbrine. The organic phase is dried with MgSO₄, filtered and concentrated.The residue is dissolved in DMSO (4 mL) and aqueous NaOH (2.5 N, 1.0 mL,2.5 mmol) is added. The mixture is allowed to stir 2 hours at ambienttemperature, then is acidified with AcOH and purified by preparativeHPLC to isolate compound 1031 (Table 1).

Example 2D Preparation of Compound 2011, Table 2

Step 1:

To a mixture of compound 2d1 (39.01 g, 239 mmol) and anhydrous DMF (800mL) under Ar is added N-iodosuccinimide (4.89 g, 244 mmol) and anhydrousK₂CO₃ (33.72 g, 244 mmol) and the mixture is allowed to stir at 60° C.for 3 hours. The mixture is cooled to ambient temperature, filtered andconcentrated under reduced pressure. The residue is dissolved in DCM (1L) and the organic phase is washed with brine. The aqueous phase isadjusted to pH 4 by the addition of 2M HCl then extracted with DCM (1L). The combined organic extracts are washed with brine (2 L) and driedover Na₂SO₄. The mixture is concentrated to approx 300 mL and cooledovernight in a fridge. The precipitated solid is removed by filtrationand dried to provide aryl iodide 2d2.

Step 2:

A mixture of compound 2d2 (115.7 g, 400 mmol) and PhPOCl₂ (668.6 g, 343mmol) under N₂ is stirred at 136° C. overnight, then cooled to roomtemperature and added slowly to 3 L of crushed ice. The aqueous mixtureis adjusted to pH 6 and filtered. The aqueous filtrate is extracted withDCM (3 L) then the organic phase is washed with saturated NaHCO₃ andbrine, dried over Na₂SO₄, filtered and concentrated to provide compound2d3.

Step 3:

A mixture of compound 1a9 (Example 1A) (62.7 g, 0.19 mol), compound 2d3(66.7 g, 0.22 mol), anhydrous K₂CO₃ (65 g, 0.47 mol) and anhydrous DMSO(250 mL) is heated at 100° C. for 2 hr. The mixture is cooled to RT,filtered and the solid is washed with EtOAc. The filtrate is dilutedwith EtOAc (4 L), washed with saturated NH₄Cl and brine, dried overMgSO₄ and concentrated. The residue is purified by flash chromatographyon silica gel (95:5 hexane/EtOAc to 7:3 Hexane/EtOAc) to affordbiarylether 2d4.

Step 4:

To a mixture of compound 2d4 (125 mg, 0.21 mmol), THF (6.0 mL), MeOH(3.0 mL) and H₂O (1.0 mL) is added LiOH (5N, 300 μL, 1.5 mmol) at 0° C.The mixture is allowed to react at 0° C. for 15 minutes, then allowed tostir at room temperature overnight. The mixture is diluted with EtOAcand acidified with 1N HCl, and the organic extract is washed with waterand brine, dried (MgSO₄) and concentrated to provide compound 2011.

Example 2E Preparation of Compound 1008, Table 1

Step 1:

A mixture of compound 2e1 (64 mg, 0.30 mmol), morpholine (0.027 mL, 0.31mmol) and triethylamine (0.050 mL, 0.36 mmol) in DMF (1 mL) is stirredovernight at ambient temperature. The mixture is then diluted with EtOAcand successively washed with water (4×) and brine. The organic phase isdried with MgSO₄, filtered and concentrated to afford intermediate 2e2.

Step 2:

Intermediate 2e2 and phenol 1a9 (Example 1A) are coupled to synthesizecompound (Table 1) using the procedure of Example 2B.

Example 2F Preparation of Compound 1010, Table 1

Step 1:

A mixture of compound 2e1 (Example 2E) (32 mg, 0.15 mmol),4-pyridylboronic acid (18 mg, 0.15 mmol), Cs₂CO₃ (72 mg, 0.22 mmol) andPd(PPh₃)₄ (9 mg, 0.01 mmol) in DMF (1 mL) is degassed and heated at 100°C. overnight. The mixture is poured into water and extracted three timeswith EtOAc. The combined organic extracts are washed with water (4×) andbrine, dried with MgSO₄, then passed through a short pad of silica gel,eluting with excess EtOAc. After concentration, the crude product ispurified by flash chromatography (15 to 50% EtOAc-hexane) to affordcompound 2f1.

Step 2:

Intermediate 2f1 and phenol 1a9 (Example 1A) are coupled to synthesizecompound 1010 (Table 1) using the procedure of Example 2B.

Example 3A Preparation of Compound 1028, Table 1

A mixture of phenol 1a9 (Example 1A) (60 mg, 0.18 mmol), compound 3a1(22 mg, 0.15 mmol) and K₂CO₃ (50 mg, 0.36 mmol) in DMSO (1 mL) isallowed to stir at 100° C. for 20 h. Morpholine (0.031 mL, 0.36 mmol) isadded and the mixture is stirred at 100° C. for an additional 20 h. Thismixture is allowed to cool to 50° C. and aqueous NaOH (2.5 N, 0.72 mL,1.8 mmol) is added. After 1 hour, the mixture is acidified with TFA andpurified by preparative HPLC to afford compound 1028 (Table 1).

Example 3B Preparation of Compound 1007, Table 1

Step 1:

Phenol 1a9 (Example 1A) (200 mg, 0.60 mmol) and compound 3b1 (90 mg,0.72 mmol) are combined in DMSO (2 mL). Anhydrous K₂CO₃ (200 mg, 1.5mmol) is added and the mixture is stirred at 100° C. for 1 hour. Furthercompound 3b1 (50 mg 0.4 mmol) is added and stirring is continued at 100°C. for 45 minutes. The mixture is cooled to ambient temperature, dilutedwith EtOAc, and washed with water (x2) and brine (x2). The organic phaseis dried over NaCl and Na₂SO₄, filtered and concentrated in vacuo.Purification by flash chromatography (2:3 EtOAc/hexanes) affordsintermediate 3b2.

Step 2:

To a mixture of aldehyde 3b2 (160 mg, 0.36 mmol), Deoxofluor™ (0.12 mL,0.65 mmol) and anhydrous DCM (1 mL) is added anhydrous MeOH (3 μL, 0.07mmol, 0.2 eq.) and the mixture is stirred 30 h at ambient temperature.The mixture is diluted with DCM and carefully washed with saturatedaqueous NaHCO₃. The organic layer is dried over NaCl/Na₂SO₄, filteredand concentrated in vacuo. The residue is purified by flashchromatography (2:3 EtOAc/hexane) and a portion of the purified residue(60 mg, 0.1 mmol) is combined with aqueous NaOH (2.5 M, 0.28 mL, 0.7mmol) in DMSO (1 mL). The mixture is stirred at ambient temperature for1 hour, then diluted with water (5 mL) and added to rapidly stirred 1Naqueous HCl (100 mL). The resulting solid is collected by suctionfiltration through a 45 μm filter membrane and dried in vacuo to affordinhibitor 1007 (Table 1).

Example 3C Preparation of Compound 1029, Table 1

Step 1:

To a mixture of compound 3c1 (38 mg, 0.16 mmol) and dry DMSO (1 mL) issuccessively added K₂CO₃ (55 mg, 0.4 mmol) and phenol 1a9 (Example 1A)(53 mg, 0.16 mmol). The reaction mixture is stirred at 55° C. for 1 h 15min and then at 70° C. for 16 h. The reaction mixture is poured intowater and extracted with EtOAc (3×). The combined organic extract issuccessively washed with water (4×) and brine, dried with MgSO₄,filtered and concentrated to afford intermediate 3c2.

Step 2:

A mixture of compound 3c2 (83 mg, 0.15 mmol) and 10% palladium on carbon(25 mg) in EtOAc (4 mL) is allowed to stir overnight at ambienttemperature under 1 atm of H₂. The mixture is filtered and concentratedto provide compound 3c3.

Step 3:

To a mixture of dianiline 3c3 (39 mg, 0.08 mmol) and DMF (1 mL) issuccessively added DIPEA (0.040 mL, 0.23 mmol), 2-methoxyacetic acid(0.006 mL, 0.08 mmol) and HATU (35 mg, 0.09 mmol). The mixture isallowed to stir overnight at ambient temperature, then is diluted withEtOAc and successively washed with 10% aq. citric acid, water, saturatedaq. NaHCO₃, water and brine. The organic phase is dried with MgSO₄,filtered and concentrated to afford intermediate 3c4.

Step 4:

A mixture of compound 3c4 (45 mg, 0.08 mol), methanol (1 mL) and 4 NHCl/dioxane (1 mL) is heated at 75° C. for 1 h. The mixture isconcentrated and the residue dissolved in DMSO. Aqueous NaOH (5 N, 0.16mL, 0.78 mmol) is added and the mixture is stirred for 30 min. at 55° C.then AcOH (300 μL) is added. The mixture is purified by preparative HPLCto isolate compound 1029 (Table 1).

Example 3D Preparation of Compound 1035, Table 1

Step 1:

To a mixture of compound 3d1 (508 mg, 2.3 mmol) and dry DMSO (3 mL) aresuccessively added CH₃NH₂.HCl (305 mg, 4.5 mmol) and Et₃N (0.79 mL, 5.6mmol). The reaction mixture is stirred at ambient temperature for 3.5 hand then at 70° C. overnight. The mixture is poured into water andextracted with EtOAc (3×). The combined organic layers are washed withwater (4×) and brine, dried with MgSO₄, filtered and concentrated.Purification by flash chromatography (2% EtOAc-hexanes) affords compound3d2.

Step 2:

Bromine (0.012 mL, 0.24 mmol) is added to a mixture of aniline 3d2 (53mg, 0.24 mmol) and glacial AcOH (0.5 mL). The mixture is heated to 70°C. and allowed to stir 5 hours. Excess Br₂ (5 μL, 0.1 mmol) is added andstirring is continued for an additional hour at 70° C. Concentration ofthe mixture provides compound 3d3.

Step 3:

To a mixture of compound 3d3 (72 mg, 0.24 mmol) and absolute MeOH isadded SnCl₂.2H₂O (540 mg, 2.4 mmol) and the mixture is heated at refluxfor 3 hours, then concentrated. The residue is taken up in EtOAc andpoured into saturated aqueous NH₄Cl. The aqueous layer is extractedtwice more with EtOAc and the combined organic extracts are filteredthrough a short pad of Celite™. The organic phase is washed with waterand brine, dried with MgSO₄, filtered and concentrated to affordcompound 3d4.

Step 4:

To a mixture of compound 3d4 (60 mg, 0.22 mmol) and DMF (1 mL), aresuccessively added DIPEA (0.12 mL, 0.67 mmol), 2-methoxyacetic acid(0.021 mL, 0.27 mmol) and HATU (100 mg, 0.27 mmol). The reaction mixtureis stirred for 6 hours at ambient temperature then diluted with EtOAcand successively washed with 10% aq. citric acid, water, saturated aq.NaHCO₃, water and brine. The organic phase is dried with MgSO₄, filteredand concentrated to provide compound 3d5.

Step 5:

A mixture of compound 3d5 (76 mg, 0.22 mmol) and glacial AcOH (2 mL) isheated at 60° C. for 6 hours on a J-Kem® orbital shaker (set at 250rpm). The mixture is concentrated and the residue is purified by flashchromatography (1:1 to 2:1 EtOAc/Hex) to afford benzimidazole 3d6.

Step 6:

The following procedure was adapted from: Elizabeth Buck, E.; Song, Z.J. Organic Syntheses 82, 2005, 69.

In a screw cap reaction vessel purged with N₂, a mixture ofbromobenzimidazole 3d6 (41 mg, 0.13 mmol), phenol 1a9 (Example 1A) (42mg, 0.13 mmol), CuCl (3 mg, 0.03 mmol), Cs₂CO₃ (83 mg, 0.25 mmol) and2,2,6,6-tetramethylheptane-3,5-dione (0.003 mL, 0.01 mmol) in anhydrousNMP (1 mL) is agitated with a J-Kem® orbital shaker (270 rpm) at 120° C.for a total of 20 hours. The mixture is acidified with AcOH and purifiedby preparative HPLC to afford compound 1035 (Table 1).

Example 3E Preparation of Compound 1036, Table 1

Step 1:

To a mixture of compound 3e1 (100 mg, 0.45 mmol) and dry DMF (2 mL) aresuccessively added Cs₂CO₃ (218 mg, 0.67 mol) and CH₃I (0.042 mL, 0.67mmol). The mixture is stirred for 1 hour at ambient temperature, pouredinto water and extracted with EtOAc. The organic extract is washed withwater (4×) and brine, dried with MgSO₄, filtered and concentrated toafford compound 3e2.

Step 2:

Compound 3e2 is converted to compound 1036 (Table 1) using theprocedures of Example 3D, steps 3-6.

Example 4A Preparation of Compound 2010, Table 2

To a mixture of compound 2011 (Example 2D) (40 mg, 0.07 mmol) andanhydrous DMF (2 mL), are added Zn(CN)₂ (16 mg, 0.14 mmol) and Pd(PPh₃)₄(8.1 mg, 0.01 mmol). The mixture is degassed with Ar and allowed to stirat 110° C. overnight. The mixture is acidified with TFA and purified bypreparative HPLC to isolate compound 2010 (Table 2).

Example 4B Preparation of Compound 2003, Table 2

A mixture of racemic BINAP (7.5 mg, 0.012 mmol) and Pd(OAc)₂ (2.7 mg,0.012 mmol) is sonicated for 10 minutes in dry toluene (1.5 mL). Thismixture is combined with a mixture of compound 2d4 (Example 2D) (75 mg,0.12 mmol), morpholine (13.9 mg, 0.16 mmol) and Cs₂CO₃ (0.20 g, 0.62mmol) in dry toluene (2 mL) and the resulting mixture is stirred at 105°C. for 3.5 h. The mixture is allowed to cool to ambient temperature,diluted with EtOAc, washed with water, saturated aqueous NaHCO₃ andbrine, dried (MgSO₄) and filtered. The filtrate is concentrated underreduced pressure and the residue mixed with THF (3.0 mL), MeOH (1.5 mL)and H₂O (0.5 mL). Aqueous LiOH (5N, 0.40 mL, 2.0 mmol) is added at 0° C.and the mixture is allowed to stir at ambient temperature overnight. Themixture is acidified with TFA and purified by preparative HPLC toprovide compound 2003 (Table 2).

Example 4C Preparation of Compound 2069, Table 2

Step 1:

The following procedure is adapted from reference: Takagi, K. Chem.Lett. 1985, 1307. To a mixture of iodoarene 2d4 (Example 2D) (270 mg,0.45 mmol) in anhydrous DMF (2 mL) are added thiourea (54 mg, 0.71mmol), NiBr₂ (11 mg, 0.05 mmol) and NaBH₃CN (4.5 mg, 0.07 mmol). Themixture is heated to 120° C. in a microwave for 15 minutes and cooled toambient temperature and diluted with DMF (3 ml). Aqueous NaOH (0.5 N, 3mL) is added slowly and the mixture is stirred vigorously for 15 minutesand partitioned between aqueous 1 N HCl and EtOAc. The organic phase iswashed with water and brine, dried with MgSO₄, filtered and concentratedunder reduced pressure to provide compound 4c1.

Step 2:

A mixture of compound 4c1 (205 mg, 0.4 mmol), DBU (0.090 mL, 0.6 mmol)and MeI (0.038 mL, 0.6 mmol) in MeCN (4 mL) is stirred overnight atambient temperature. The mixture is diluted with EtOAc (50 mL) andwashed with 1 N aqueous HCl, water, 1 N aqueous NaOH, water, aqueousthiosulphate and brine. The organic phase is dried with MgSO₄, filteredand concentrated under reduced pressure to provide compound 4c2.

Step 3:

Aqueous LiOH (5 N, 0.18 mL, 0.9 mmol) is added to a mixture ofmethylthioether 4c2 (95 mg, 0.18 mmol) in THF (4 mL), MeOH (2 mL) andwater (0.1 mL). The mixture is stirred at ambient temperature for 4hours then heated to 50° C. for 5 hours and allowed to cool to ambienttemperature. The mixture is acidified with 1N HCl, diluted with EtOAcand washed with water and brine. The organic phase is dried with MgSO₄,filtered and concentrated under reduced pressure. The residue is takenup in a mixture of acetone and water (5:2; 7 mL), Oxone™ (572 mg, 0.93mmol) is added and the mixture is stirred at ambient temperature for 2.5days. The mixture is then diluted with EtOAc and ether (3:2) and washedwith 1 N aqueous HCl, water and brine. The organic phase is dried withMgSO₄, filtered and concentrated under reduced pressure. The residue istaken up in DMSO and purified by preparative HPLC to afford compound2069 (Table 2).

Example 5A Preparation of Compound 2002, Table 2

To a mixture of compound 2011 (Example 2D) (110 mg, 0.19 mmol) inanhydrous DMF (3 mL), is added 1-ethoxyvinyltri-n-butyltin (0.085 mL,0.25 mmol) and bis(tri-tert-butylphosphino)palladium(0) (9.7 mg, 0.02mmol). The mixture is degassed with Ar and allowed to stir at 100° C.for 45 minutes. The mixture is allowed to cool to ambient temperature,MeCN (4 mL) and 1N HCl (4 mL) are added and stirring is continued atambient temperature for 15 minutes. The mixture is concentrated underreduced pressure and DMSO (4 mL) is added to the resulting residue. Themixture is filtered and purified by preparative HPLC to isolate compound2002 (Table 2).

Example 5B Preparation of Compound 2004, Table 2

Step 1:

Intermediate 5b1 was prepared from compound 2d4 (Example 2D) utilizingthe procedure described in Example 5A.

Step 2:

NaBH₄ (9.1 mg, 0.24 mmol) is slowly added to a mixture of compound 5b1(50 mg, 0.10 mmol) and MeOH (6 mL), and the mixture is stirred atambient temperature overnight. The mixture is diluted with EtOAc andwashed with 1N HCl, water, saturated aqueous NaHCO₃ and brine, driedwith MgSO₄, filtered and concentrated under reduced pressure. Theresidue is mixed with THF (2 mL), MeOH (1 mL) and water (0.5 mL), andaqueous LiOH (5 N, 0.20 mL, 1.0 mmol) is added. The mixture is allowedto stir overnight at ambient temperature, then is acidified with TFA andconcentrated. DMSO (2 ml) is added to the residue and purification ofthe mixture by preparative HPLC affords compound 2004 (table 2).

Example 5C Preparation of Compound 2154, Table 2

A mixture of compound 5b1 (Example 5B) (48 mg, 0.09 mmol), NaBH₄ (5.3mg, 0.14 mmol), AcOH (0.050 mL, 0.88 mmol) and morpholine (0.010 mL,0.11 mmol) in EtOH (1 mL) is heated for 20 hours at 60° C. Excess NaBH₄(2 mg, 0.05 mmol) and morpholine (0.017 mL, 0.18 mmol) are added andstirring is continued for an additional 20 hours at 60° C. Aqueous NaOH(2.5 N, 0.60 mL, 1.5 mmol) is added and the mixture is stirred for 1hour at 50° C. After acidification with AcOH, the mixture is purified bypreparative HPLC to isolate compound 2154 (Table 2).

Example 6A Preparation of Compound 2103, Table 2

Step 1:

The procedure is adapted from a protocol described in: Hennessy, E. J.;Buchwald, S. L. Org. Lett. 2002, 4, 269.

A mixture of compound 2d4 (Example 2D) (2.0 g, 3.3 mmol), dibenzylmalonate (2.5 g, 9.9 mmol), CuI (76 mg, 0.4 mmol), 2-phenylphenol (68mg, 0.4 mmol), Cs₂CO₃ (4.1 g, 12.5 mmol) in anhydrous THF (30 mL) isdegassed with Ar 15 minutes, then stirred at 70° C. for 16 hours. ExcessCuI (76 mg, 0.4 mmol) and 2-phenylphenol (68 mg, 0.4 mmol) are added andstirring is continued at 70° C. for an additional 20 hours. The mixtureis diluted in EtOAc, washed with saturated aqueous NH₄Cl and brine, andconcentrated. The residue is taken up in EtOH (20 mL) and 10% Pd/C (0.4g) is added. The mixture is stirred under 1 atm of H₂ for 2 hours atambient temperature and filtered through a pad of Celite™. The filtrateis stirred at 80° C. for 1 hour, allowed to cool to ambient temperatureand concentrated under reduced pressure. The residue is purified byflash chromatography (1:1 EtOAc/Hex) to afford compound 6a1.

Step 2:

To a mixture of compound 6a1 (900 mg, 1.7 mmol) in CH₂Cl₂ (24 mL) isadded oxalyl chloride (0.21 mL, 2.4 mmol) and DMF (0.060 mL, 0.8 mmol)and the mixture is allowed to stir for 1 hour at room temperature. Themixture is concentrated and the residue is taken up in CH₂Cl₂ (30 mL).CH₂N₂ (0.35 M in Et₂O, 46 mL, 16 mmol) is added dropwise with stirringand stirring is continued for 30 minutes. The mixture is concentratedunder reduced pressure and the residue is taken up in THF (24 mL). 48%aqueous HBr (1.8 mL, 16 mmol) is added and the mixture is allowed tostir for 20 minutes. The mixture is concentrated under reduced pressureand diluted with EtOAc. The organic phase is washed with water,saturated aqueous NaHCO₃ and brine, dried over MgSO₄, filtered andconcentrated under reduced pressure to provide compound 6a2.

Step 3:

A mixture of bromoketone 6a2 (60 mg, 0.1 mmol) and thioacetamide (14 mg,0.19 mmol) in i-PrOH is allowed to stir at 70° C. for 1 hour. Themixture is allowed to cool to ambient temperature and NaOH (2.5 N, 0.18mL, 0.44 mmol) is added. The mixture is stirred at 40° C. for 5 hours,then diluted with water and acidified with HCl. The solid is collectedby filtration and washed with excess water, then taken up in DMSO andpurified by preparative HPLC to afford compound 2103 (Table 2).

Example 7A Preparation of Intermediate 7a5

Step 1:

To a mixture of compound 2d4 (Example 2D) (40 g, 66.2 mmol) in anhydrousTHF (280 mL) are added vinyltributyltin (23 mL, 25 g, 78.8 mmol) andPdCl₂(PPh₃)₂ (4.8 g, 6.8 mmol). The mixture is degassed with Ar for 5minutes, then heated at reflux for 4-6 hours. The solvent is removedunder reduced pressure and the residue is purified by flashchromatography (gradient from 19:1 to 3:2 Hexane/EtOAc) to affordintermediate 7a1.

Step 2:

To a solution of the alkene 7a1 (40.3 g, 79.9 mmol) in acetone (710 mL)are added tert-BuOH (176 mL), water (88 mL), 4-N-methylmorpholineoxidemonohydrate (60% solution in water, 21 mL, 120 mmol) and OSO₄ (2.5 wt %in t-BuOH, 13.3 mL, 1.06 mmol). The mixture is stirred overnight atambient temperature, then is concentrated and taken up in EtOAc (4 L).The organic phase is washed with 2M HCl (2×1 L), water, saturatedaqueous NaHCO₃ (1 L) and brine. Activated carbon and Na₂SO₄ are added tothe organic phase and the mixture is stirred for 10 minutes. The mixtureis filtered through a pad of Celite™ then concentrated to affordintermediate 7a2.

Step 3:

Sodium periodate (25 g, 116.9 mmol) is added to a chilled (0° C.)mixture of the diol 7a2 (40.6 g, 75.4 mmol) in THF (710 mL) and water(270 mL). The mixture is left 5 minutes at 0° C., then stirring iscontinued at room temperature for 4 h. Additional sodium periodate (3.3g, 15.4 mmol, 0.2 eq) is added and stirring is continued for 2 hours.The mixture is diluted with ether/EtOAc (1.8 L/3.6 L) then washed withwater and brine, dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue is purified by flash chromatography toafford intermediate 7a3.

Step 4:

Sodium borohydride (4.4 g, 116 mmol, 2 eq) is added slowly to a mixtureof aldehyde 7a3 (30.7 g, 60.6 mmol) and MeOH (300 mL). The mixture isstirred for 2 hours at ambient temperature, then diluted with EtOAc andcarefully washed with 1N HCl, saturated aqueous NaHCO₃ and brine. Theorganic phase is dried over Na₂SO₄, filtered and concentrated underreduced pressure to afford intermediate 7a4.

Step 5:

Thionyl chloride (5.5 mL, 8.1 mmol) is added slowly to a mixture ofalcohol 7a4 (19 g, 37.4 mmol), anhydrous CH₂Cl₂ (450 mL)and DMF (9 mL).The mixture is stirred 30 minutes at ambient temperature, then dilutedwith EtOAc (1.5 L) and washed with saturated aqueous NaHCO₃ and brine.The organic phase is dried with Na₂SO₄, filtered and concentrated togive intermediate 7a5.

Example 8A Preparation of Compound 2005, Table 2

Diazomethane in ether (4 mL) is slowly added to a chilled (0° C.)mixture of alkene 7a1 (Example 7A) (26 mg, 0.05 mmol) in ether (2 mL).Pd(OAc)₂ (2 mg, 0.01 mmol) is added and the mixture is stirred atambient temperature for 1.5 hours. The mixture is concentrated underreduced pressure, and THF (2 mL), MeOH (1 mL) and water (0.2 mL) areadded to the residue followed by aqueous LiOH (5 N, 0.6 mL, 3.0 mmol).The mixture is stirred at ambient temperature for 2.5 days. DMSO (1.5mL) and excess aqueous LiOH (5 N, 0.3 mL, 1.5 mmol) are added andstirring is continued at ambient temperature overnight. The mixture isacidified with TFA and concentrated under reduced pressure. The residueis purified by preparative HPLC to isolate compound 2005 (Table 2).

Example 8B Preparation of Compound 2007, Table 2

To a mixture of alkene 7a1 (Example 7A) (23 mg, 0.05 mmol) in MeOH (2mL) and EtOAc (4 mL) is added 10% palladium on carbon (2 mg). Themixture is stirred for 2.5 days under H₂ (˜1 atm), then filtered andconcentrated to dryness. The residue is taken up in THF (2 mL), MeOH (1mL) and water (0.2 mL). Aqueous LiOH (5 N, 0.4 mL, 2.0 mmol) is addedand the mixture is stirred at ambient temperature overnight. DMSO (1.0mL) and excess aqueous LiOH (5 N, 0.2 mL, 1.0 mmol) are added andstirring is continued at 50° C. for 3 hours. The mixture is acidifiedwith TFA and concentrated under reduced pressure. The residue ispurified by preparative HPLC to isolate compound 2007 (Table 2).

Example 9A Preparation of Compound 2120, Table 2

A mixture of aldehyde 7a3 (Example 7A) (50 mg, 0.1 mmol) and2-aminopyrazine (38 mg, 0.4 mmol) in AcOH (0.5 mL) is stirred at 80° C.for 2 hours. The mixture is allowed to cool to ambient temperature,NaCNBH₃ (7.9 mg, 0.13 mmol) is added and the mixture is stirred for 15minutes, then concentrated under a stream of N₂. Aqueous NaOH (2.5N,0.60 mL, 1.5 mmol) is added to the residue and the mixture is allowed tostir at 50° C. for 2 hours, then purified by preparative HPLC to isolatecompound 2120 (Table 2).

Example 10A Preparation of Compound 2026, Table 2

A mixture of intermediate 7a5 (Example 7A) (25 mg, 0.05 mmol), indole(8.2 mg, 0.07 mmol), Cs₂CO₃ (23 mg, 0.07 mmol) and KI (3 mg, 0.02 mmol)in DMF (1 mL) is agitated on a J-Kem® orbital shaker (250 rpm) at 70° C.overnight. DMSO (0.5 mL) is added followed by aqueous NaOH (5 N, 0.10mL, 0.5 mmol) and the mixture is stirred at 55° C. for 1 hour. Themixture is acidified with AcOH, then purified by preparative HPLC toisolate compound 2026 (Table 2).

Example 10B Preparation of Compounds 2047 and 2057, Table 2

Step 1:

A mixture of compound 7a5 (Example 7A) (25 mg, 0.05 mmol),3-pyrrolidinol (0.006 mL, 0.07 mmol) and Et₃N (0.010 mL, 0.07 mmol) inTHF (1 mL) is agitated on a J-Kem® orbital shaker (250 rpm) at 70° C.overnight. The mixture is concentrated under a stream of N₂ then takenup in DMSO (0.5 mL). Aqueous NaOH (5 N, 0.10 mL, 0.5 mmol) is added andthe mixture is stirred at 55° C. for 1 hour. The mixture is acidifiedwith AcOH and purified by preparative HPLC to isolate compound 2047(Table 2).

Step 2:

A mixture of compound 2047 (12 mg, 0.02 mmol) and Dess-Martinperiodinane (7.6 mg, 0.02 mmol) in DCM/CH₃CN (1:1, 1 mL) is stirred atambient temperature for 20 hours. An additional portion of Dess-Martinperiodinane (7.6 mg, 0.02 mmol) is added and is stirring is continuedfor a further 20 hours. The mixture is concentrated under reducedpressure and the residue is purified by preparative HPLC to affordcompound 2057 (Table 2).

Example 10C Preparation of Compound 2153 (Table 2)

Step 1:

A mixture of compound 7a5 (Example 7A) (9.5 g, 18.05 mmol), NaN₃ (2.16g, 33.4 mmol) and 60% (v/v) acetone-water (90 mL) is stirred at refluxunder Ar overnight. The mixture is concentrated under reduced pressureand the residue is extracted with EtOAc (1 L) and washed with water(4×). The organic phase is dried over MgSO₄, filtered and concentratedunder reduced pressure to provide compound 10c1.

Step 2:

Argon is bubbled though a mixture of compound 10c1 (9.68 g, 18.14 mmol)in methanol (100 mL) for 10 minutes and the mixture is added to Pd/C(10%, 1 g) under Ar. H₂ is bubbled through the stirred mixture for 2.5hours. The mixture is filtered through Celite™ and rinsed with MeOH. Thefiltrate is concentrated to dryness and the residue is purified by flashcolumn chromatography (SiO₂, MeOH/DCM: 5/95) to isolate the free amine.A mixture of the amine and 2M HCl solution in Et₂O (30 mL) is stirred atroom temperature for 1 hour. The hydrochloride salt 10c2 is collected byfiltration, rinsed with diethyl ether and air dried.

Step 3:

To a mixture of compound 10c2 (25 mg, 0.049 mmol) and DMF (0.50 mL) isadded cyclopropanesulfonyl chloride (6.3 μL, 0.058 mmol) and Et₃N (16.9μL, 0.121 mmol). The mixture is agitated on an orbital shaker (350 rpm)overnight at room temperature. NaOH (5N, 100 μL, 0.50 mmol) is added,the mixture is heated at 50° C. for 1 h, then acidified with AcOH andpurified by preparative HPLC to give compound 2153 (Table 2).

Example 10D Preparation of Compound 2159 (Table 2)

To a mixture of compound 10c2 (Example 10C) (25 mg, 0.046 mmol, 1equivalent) in DMF (0.5 mL) is added (CH₃)₂CH—NCO (1.3 equivalents). Themixture is stirred at room temperature until complete as determined byHPLC analysis. 5N NaOH (0.1 mL, 10 equivalents) is added and the mixtureis heated to 50° C. for 1 h, then acidified with AcOH. Purification byreversed-phase HPLC provides compound 2159 (Table 2).

Example 10E Preparation of Compound 2161 (Table 2)

To a mixture of compound 10c2 (Example 10C) (25 mg, 0.046 mmol, 1equivalent) in THF (0.5 mL) is added DIEA (12 μL, 1.5 equivalents)followed by ethyl chloroformate (5.3 μL, 1.2 equiv.). The mixture isstirred at room temperature overnight, then concentrated under reducedpressure. The residue is mixed with DMSO (0.5 mL), 5N NaOH (0.1 mL, 11equivalents) is added and the mixture is heated at 50° C. for 45 min.The mixture is acidified using AcOH and purified by reversed-phase HPLCto provide compound 2161 (Table 2).

Example 10F Preparation of Compound 2188 (Table 2)

To a mixture of compound 10c2 (Example 10C) (50 mg, 0.091 mmol) and DCM(1 mL) is added ethyl chloroformate (12 μL, 0.126 mmol) followed by Et₃N(40 μL, 0.287 mmol). The reaction mixture is stirred at room temperatureovernight and concentrated under a stream of argon, and the residue ismixed with DMF (1 mL).

Half of the mixture is added to a vial containing NaH (60% oildispersion, 6 mg, 3.3 equiv.) and the mixture is stirred for 5 min atroom temperature. Iodomethane (10 μL, 3.5 equiv.) is added and stirringis continued at room temperature for 5 h. 5N NaOH (10 equiv.) is addedand the mixture stirred an additional 14 h at room temperature andpurified by preparative HPLC to provide compound 2188 (Table 2).

Example 11A Preparation of Compound 2039, Table 2

A mixture of intermediate 7a5 (Example 7A) (25 mg, 0.05 mmol),2-mercaptoimidazole (7.0 mg, 0.07 mmol), Cs₂CO₃ (23 mg, 0.07 mmol) andDMF (1 mL) is agitated on a J-Kem® orbital shaker (250 rpm) at 70° C.overnight. DMSO (0.5 mL) is added followed by aqueous NaOH (5 N, 0.10mL, 0.5 mmol) and the mixture is stirred at 55° C. for 1 hour. Themixture is acidified with AcOH, then purified by preparative HPLC toisolate compound 2039 (Table 2).

Example 11B Preparation of Compound 2071, Table 2

Step 1:

A mixture of intermediate 7a5 (Example 7A) (55 mg, 0.1 mmol), KI (3 mg,0.02 mmol), NaSMe (11 mg, 0.16 mmol) and Et₃N (0.031 mL, 0.23 mmol) inanhydrous DMF (1.5 mL) is stirred at 70° C. for 1.5 hours, then cooledto ambient temperature. The mixture is diluted with EtOAc and washedwith 1 N aqueous HCl, water, saturated aqueous NaHCO₃ and brine, driedwith MgSO₄, filtered and concentrated under reduced pressure to providecompound 11b1.

Step 2:

Oxone™ (298 mg, 0.49 mmol) is added to a mixture of compound 11b1 (52mg, 0.1 mmol) in acetone/water (3:1; 8 mL). The mixture is stirred atambient temperature for 2 hours, then diluted with EtOAc and washed withwater and brine. The organic phase is dried with MgSO₄, filtered andconcentrated under reduced pressure. The residue is taken up in mixtureof DMSO (2 mL), MeOH (1 mL) and water (0.2 mL). Aqueous LiOH (5 N, 0.20mL, 1.0 mmol) is added and the mixture is stirred at ambient temperatureovernight followed by 4 hours at 50° C. The mixture is allowed to coolto ambient temperature then is acidified with TFA, concentrated andpurified by preparative HPLC to isolate compound 2071 (Table 2).

Example 12A Preparation of Compound 2084, Table 2

Step 1:

A mixture of compound 7a5 (Example 7A) (30 mg, 0.06 mmol), FeCl₃ (9.7mg, 0.06 mmol) and anisole (6.1 mg, 0.06 mmol) in CH₂Cl₂ (2 mL) isheated at 100° C. for 15 minutes in a microwave. The mixture isconcentrated, then taken up in DMSO and purified by preparative HPLC toisolate intermediate 12a1.

Step 2:

A mixture of compound 12a1 (6 mg, 0.01 mmol), compound 1a7 (Example 1A)(13 mg, 0.08 mmol) and pyridine (0.3 mL) is heated to 180° C. for 12minutes in a microwave. The mixture is purified by preparative HPLC toisolate compound 2084 (Table 2).

Example 13A Preparation of Compound 2056, Table 2

Step 1:

The procedure used is adapted from: Abdel-Magid, A. F.; Carson, K. G.;Harris, B. D.; Maryanoff, C. A.; Shah, R. D. J. Org. Chem. 1996, 61,3849. To a mixture of compound 13a1 (10.0 g, 36 mmol) and CH₂Cl₂ (212mL) is added 2-methoxypropene (13.8 mL, 144 mmol) followed by NaBH(OAc)₃(15.3 g, 72 mmol) and AcOH (8.2 mL, 144 mmol). The mixture is stirredovernight at ambient temperature, then diluted with EtOAc and washedwith NaHCO₃ and brine. The organic phase is dried with MgSO₄, filteredand concentrated under reduced pressure. The residue is subjected toflash chromatography (1:9 EtOAc/Hex) to isolate compound 13a2.

Step 2:

To a mixture of compound 13a2 (10.2 g, 32 mmol) in anhydrous pyridine(160 mL) is added compound 1a7 (Example 1A) (11.3 g, 70 mmol) and DMAP(˜0.44 g). The mixture is stirred at 80° C. for 2 days, then is dilutedwith EtOAc (250 mL), and washed with 1N HCl, water, saturated aqueousNaHCO₃ and brine. The organic phase is dried with MgSO₄, filtered andconcentrated under reduced pressure. The crude product is purified byflash chromatography (1:4 EtOAc/Hex) to afford amide 13a3.

Step 3:

The procedure used is adapted from: Takagi, K. Chem. Lett. (1985), 14:1307. A mixture of compound 13a3 (100 mg, 0.23 mmol), NiBr₂ (5.7 mg,0.03 mmol), thiourea (27 mg, 0.35 mmol) and NaCNBH₃ (2.2 mg, 0.04 mmol)in DMF (2 mL) is heated at 120° C. for 15 minutes in a microwave.Aqueous NaOH (2.5 N, 2.0 mL, 1.0 mmol) is added and the mixture isstirred for 15 minutes. The mixture is diluted with EtOAc and washedwith aqueous 1 N HCl and brine. The organic phase is dried with MgSO₄,filtered and concentrated under reduced pressure to provide compound13a4.

Step 4:

A mixture of compound 13a4 (40 mg, 0.11 mmol),2-fluoro-3-trifluoromethylpyridine (21 mg, 0.13 mmol) and K₂CO₃ (55 mg,0.40 mmol) in DMSO (1.0 mL) is stirred at 100° C. for 20 h. The mixtureis cooled to room temperature and NaOH (2.5N, 300 μL, 0.75 mmol) isadded. The mixture is stirred at 40° C. for 1 h, acidified with AcOH andpurified by preparative HPLC to provide compound 2056 (Table 2).

Example 14A Preparation of Compound 1004, Table 1

-   Reference: Tanaka, K.; Suzuki, T.; Maeno, S.; Mitsuhashi, K. J.    Heterocycl. Chem. 1986, 23, 1537.    Step 1:

A mixture of compound 14a1 (500 mg, 4.62 mmol) and1-ethoxy-2,2,2-trifluoroethanol (667 mg, 4.63 mmol) is heated at 80° C.for 2 h, then cooled and diluted with Et₂O. The mixture is washed with1N HCl, water and brine, and the organic extract is dried (MgSO₄),filtered and concentrated to give compound 14a2.

Step 2:

A mixture of aqueous glyoxal (40%, 2.0 g, 13.8 mmol) and n-BuOAc (10 mL)is dried over MgSO₄ and filtered. To the filtrate is added compound 14a2(853 mg, 4.5 mmol), AcOH (50 μL) and MgSO₄ (462 mg, 3.8 mmol), and themixture is heated at 120° C. for 6 h. Further glyoxal is added (preparedby extracting aqueous glyoxal (40%, 27 g, 186 mmol) with EtOAc, dryingthe EtOAc extract over MgSO₄, adding n-BuOAc (10 mL) and concentratingthe solution under reduced pressure) and heating at 120° C. is continuedfor a further 3.5 h. The mixture is filtered and concentrated, and theresidue is mixed with 1N NaOH and washed with CH₂Cl₂. The aqueous phaseis acidified to pH 2 with conc. HCl and extracted three times withCH₂Cl₂. The combined organic extracts are washed with water and brine,dried (MgSO₄), filtered and concentrated. The residue is purified byflash chromatography to provide compound 14a3.

Step 3:

A mixture of compound 13a3 (Example 13A) (39 mg, 0.088 mmol), compound14a3 (20 mg, 0.088 mmol), Cs₂CO₃ (57 mg, 0.18 mmol),2,2,6,6-tetramethylheptane-3,5-dione (2.0 μL, 0.01 mmol) and CuCl (4.4mg, 0.044 mmol) in NMP (1.0 mL) under N₂ atmosphere is heated at 120° C.for 7 h on a J-Kem® orbital shaker (275 rpm). Aqueous NaOH (5N, 176 μL,0.88 mmol) is added and the mixture is heated at 50° C. for 30 minutes.AcOH is added to a total volume of 1.5 mL and the mixture is filteredand purified by preparative HPLC to provide compound 1004 (Table 1).

Example 15A Preparation of Compound 2196, Table 2

Step 1:

A mixture of carboxylic acid 15a1 (5.0 g, 27 mmol) and concentratedH₂SO₄ (4 mL) in MeOH (80 mL) is stirred at reflux for 12 hours. Themixture is concentrated under reduced pressure and poured onto a mixtureof ice and saturated aqueous NaHCO₃. The aqueous mixture is acidifiedwith citric acid and extracted twice with EtOAc. The combined organicextracts are washed with water and brine, dried with MgSO₄, filtered,and concentrated under reduced pressure. Purification by flashchromatography (3:7 EtOAc/Hexane) affords ester 15a2.

Step 2:

Compound 15a2 (10 g, 51 mmol), 2-fluoro-3-trifluoromethylpyridine (10 g,61 mmol) and K₂CO₃ (8.4 g, 61 mmol) are mixed in anhydrous DMSO (150 mL)at room temperature under an argon atmosphere. The mixture is stirred at100° C. overnight, cooled to room temperature and diluted with EtOAc (3L). The organic phase is washed with saturated NH₄Cl solution and brine,dried over MgSO₄, filtered and concentrated under reduced pressure.Addition of Et₂O and hexanes to the residue provides compound 15a3;further compound 15a3 is obtained by concentrating the filtrate andpurifying the residue by flash chromatography.

Step 3:

A mixture of compound 15a3 (12.5 g, 37 mmol), MeOH (600 mL) and Pd/C(1.4 g). is stirred at room temperature for 3.5 hours under H₂ (1 atm).The mixture is filtered through Celite™ and rinsed with MeOH. Thefiltrate is concentrated and the residue is purified by flashchromatography (gradient; 1/4 to 2/3 EtOAc/Hexanes). A mixture of thefree aniline obtained and CH₂Cl₂ (250 mL) is cooled to 0° C. and 2M HClin Et₂O (50 mL) is added. The mixture is stirred at room temperature for1 h and the hydrochloride salt 15a4 is collected by filtration, rinsedwith Et₂O and air dried.

Step 4:

To a mixture of compound 15a4 (2.1 g, 5.9 mmol) and 2-methoxypropene(2.3 mL, 24 mmol) in CH₂Cl₂ is added NaBH(OAc)₃ (2.5 g, 12 mmol)portionwise. The mixture is stirred at ambient temperature for 30minutes, then diluted with EtOAc and washed with saturated aqueousNaHCO₃ and brine. The organic phase is dried with MgSO₄, filtered andconcentrated under reduced pressure. Trituration of the residue inhexanes/ether followed by filtration, washing (hexanes) and dryingaffords compound 15a5.

Step 5:

Oxalyl chloride (2 M in DCM, 0.16 mL, 0.32 mmol) is added slowly to amixture of 4-chloro-3-methylbenzoic acid (27 mg, 0.16 mmol) in DCM (1mL). DMF (1 drop) is added and the mixture is stirred 30 minutes atambient temperature and concentrated under reduced pressure. The residueis mixed with pyridine (0.5 mL), compound 15a5 (30 mg, 0.08 mmol) isadded, and the mixture is stirred at 60° C. overnight. Aqueous NaOH (10N, 0.096 mL, 0.96 mmol) and water (0.2 mL) are added and the mixture isstirred overnight at ambient temperature, then diluted with EtOAc andwashed with 1N HCl and brine. The organic phase is dried with MgSO₄,filtered and concentrated under reduced pressure. Purification bypreparative HPLC affords compound 2196 (Table 2).

Example 16A Preparation of Compound 2124, Table 2

Step 1:

A mixture of compound 15a4 (Example 15A) (2.0 g, 5.8 mmol),tert-butylbromoacetate (4.3 mL, 29 mmol) and DIPEA (3.0 mL, 17 mmol) inDMF (20 mL) is stirred at 80° C. overnight. The mixture is diluted withEtOAc and washed with 0.5 N aqueous KHSO₄, saturated aqueous NaHCO₃ andbrine. The organic phase is dried with MgSO₄, filtered and concentratedunder reduced pressure. The residue is purified by flash chromatography(gradient; 1:9 to 1:1 EtOAc/Hex) to give compound 16a1.

Step 2:

To a mixture of 16a1 (1.6 g, 3.7 mmol) and DMAP (0.45 g, 3.7 mmol) inanhydrous pyridine (20 mL) is added compound 1a7 (Example 1A) (0.90 g,5.6 mmol). The mixture is stirred at 70° C. overnight, then is dilutedwith EtOAc and washed with 1 N HCl, saturated aqueous NaHCO₃ and brine.The organic phase is dried with MgSO₄, filtered and concentrated underreduced pressure. Trituration with 1:9 EtOAc/Hex affords amide 16a2.

Step 3:

Trifluoroacetic acid (5 mL) is slowly added to a mixture of compound16a2 (1.5 g, 2.8 mmol) and DCM (20 mL) at 0° C. The mixture is allowedto warm to ambient temperature and stir overnight, then is concentratedunder reduced pressure. The residue is mixed with DCM and concentratedtwice, then lyophilized from water and acetonitrile to afford acid 16a3.

Step 4:

To a mixture of compound 16a3 (25 mg, 0.05 mmol) and HATU (23 mg, 0.06mmol) in DMF (0.5 mL) is added pyrrolidine (0.005 mL, 0.06 mmol),followed by Et₃N (0.030 mL, 0.22 mmol). The mixture is agitated in aJ-Kem® orbital shaker (250 rpm) for 1 hour at ambient temperature.Aqueous NaOH (5 N, 0.10 mL, 0.5 mmol) is added and agitation iscontinued overnight at ambient temperature. The mixture is acidifiedwith AcOH (0.1 mL), diluted with DMSO (1 mL) and purified by preparativeHPLC to isolate compound 2124 (Table 2).

Example 16B Preparation of Compound 2149, Table 2

To a mixture of acid 16a3 (Example 16A) (50 mg, 0.1 mmol) in DMF isadded HATU (51 mg, 0.14 mmol), phenylenediamine (11 mg, 0.11 mmol) andEt₃N (0.063 mL, 0.45 mmol). The mixture is stirred overnight at ambienttemperature, then diluted with EtOAc and washed with 10% aqueous citricacid, water, saturated aqueous NaHCO₃ and brine. The organic phase isdried with MgSO₄, filtered and concentrated under reduced pressure. Theresidue is then mixed with AcOH (1 mL) and stirred at 100° C. for 1hour. After cooling to ambient temperature, the mixture is diluted withEtOAc and washed with saturated aqueous NaHCO₃, water and brine. Theorganic phase is dried with MgSO₄, filtered and concentrated underreduced pressure. The residue (55 mg, 0.1 mmol) is combined with DMSO (2mL), MeOH (1 mL) and water (0.15 mL). Aqueous NaOH (10 N, 0.097 mL, 0.10mmol) is added and the mixture is stirred overnight at ambienttemperature. The mixture is acidified with TFA and purified bypreparative HPLC to isolate compound 2149 (Table 2).

Example 17 Inhibition of NS5B RNA Dependent RNA Polymerase Activity

Representative compounds of the invention are tested for inhibitoryactivity against the hepatitis C virus RNA dependent polymerase (NS5B),according to the protocol described below.

The HCV His-NS5BΔ21 polymerase [SEQ ID NO:1] lacks the C-terminal 21amino acids and is expressed with an N-terminal hexa-histidine tag froma pET-based vector in E. coli strain JM109(DE3) and purified asdescribed in McKercher et al., (2004) Nucleic Acids Res. 32: 422-431.The homogeneous enzyme preparation is stored at −20° C. in storagebuffer (25 mM Tris/HCl pH 7.5, 300 mM NaCl, 5 mM DTT, 1 M EDTA and 30%(v/v) glycerol).

The purified His-NS5BΔ21 polymerase is reconstituted in an assay thatmeasures the incorporation of ³H-UTP during the elongation of abiotin-oligo-(U)₁₂ RNA primer annealed to a homopolymeric poly(A)template. The test compound is added first, followed by the substrate,then the enzyme. At the end of the reaction, streptavidin scintillationproximity assay (SPA) beads are added and the radioactivity from thecaptured double-stranded RNA product is quantified on TopCountinstrument (Packard). The components of the assay reaction are: 20 mMTris-HCl pH 7.5, 1 mM TCEP, 1 mM EDTA, 5 mM MgCl₂, 0.01% w/v BSA, 5% v/vDMSO, 10 μg/mL Poly(A), 1 μg/mL Biotin-oligo-(U)₁₂, 333 nM UTP, 0.01mCi/mL, (300 nM) ³H-UTP, 80 units/mL Rnasin, 12.5 nM His-NS5BΔ21polymerase and test inhibitor compound that is serially diluted over alarge concentration range. The assay is performed in 384-well plateswith a 1.5 hour incubation at 22° C., and then stopped with a solutionof 0.5 M EDTA and the products captured with Streptavidin-coated beads.Following the addition of 6 M CsCl to the bottom of each well, the plateis left at room temperature for 90 minutes before counting for 60seconds on a TopCount. The calculated % inhibition values are then usedto determine IC₅₀, slope factor (n) and maximum inhibition (I_(max)) bythe non-linear regression routine NLIN procedure of SAS.

Example 18 Specificity of NS5B RNA Dependent RNA Polymerase Inhibition

Representative compounds of the invention are tested for inhibitoryactivity against polio virus RNA dependent RNA polymerase and calfthymus DNA dependent RNA polymerase II as described in McKercher et al.,(2004) Nucleic Acids Res. 32: 422-431.

Example 19 Cell-Based Luciferase Reporter HCV RNA Replication Assay

Representative compounds of the invention are tested for activity asinhibitors of hepatitis C virus RNA replication in cells expressing astable subgenomic HCV replicon, using the assay described in WO2005/028501.

Tables of Compounds

The following tables list compounds representative of the invention.Representative compounds listed in Tables 1 and 2 below are tested inthe NS5B polymerase activity inhibition assay of Example 33, and arefound to have IC₅₀ values below 30 μM. Retention times (t_(R)) for eachcompound are measured using the standard analytical HPLC conditionsdescribed in the Examples. As is well known to one skilled in the art,retention time values are sensitive to the specific measurementconditions. Therefore, even if identical conditions of solvent, flowrate, linear gradient, and the like are used, the retention time valuesmay vary when measured, for example, on different HPLC instruments. Evenwhen measured on the same instrument, the values may vary when measured,for example, using different individual HPLC columns, or, when measuredon the same instrument and the same individual column, the values mayvary, for example, between individual measurements taken on differentoccasions.

TABLE 1

t_(R) MS Cpd R² R⁵ (min) (M + H)⁺ 1001

5.8 404.2 1002

5.2 390.2 1003

6.1 465.1 1004

7.7 530 1005

5.7 476.0 1006

5.8 475.2 1007

6.0 447.2 1008

7.5 550 1009

6.6 481 1010

5.6 542 1011

5.5 397.2 1012

5.5 422.2 1013

5.5 423.2 1014

6.2 431.2 1015

5.3 432.2 1016

5.8 432.2 1017

5.8 444.2 1018

6.7 447.2 1019

6.6 447.2 1020

6.3 456.2 1021

6.2 456.2 1022

5.6 411.3 1023

6.3 475.1 1024

6.4 475.1 1025

5.8 436.2 1026

5.4 446.2 1027

5.6 475.1 1028

5.5 483.3 1029

5.4 548 1030

6.3 482.2 1031

6.3 402.1 1032

6.1 431.1 1033

5.1 512.2 1034

5.3 542.2 1035

5.7 562.2 1036

5.8 562

TABLE 2

t_(R) MS Cpd R²³ X R⁵ R⁶ (min) (M + H)⁺ 2001 H O

7.0 465.1 2002

O

6.4 507.1 2003

O

6.5 550.1 2004

O

5.9 509.1 2005

O

7.0 505.1 2006

O

6.9 491.1 2007

O

7.0 493.1 2008

O

5.4 525.1 2009

O

5.4 577.3 2010 —CN O

6.4 490.2 2011 —I O

7.1 591.1 2012

O

5.3 572.2 2013

O

5.2 545.2 2014

O

6.2 545.2 2015

O

6.0 588.2 2016

O

5.5 586.3 2017

O

6.0 588.2 2018

O

5.8 589.2 2019

O

6.6 597.2 2020

O

5.6 600.3 2021

O

7.0 606.2 2022 —CH₂OH O

5.7 495.2 2023

O

5.6 573.2 2024

O

7.1 559.2 2025

O

6.9 573.2 2026

O

7.9 594.2 2027

O

7.2 595.2 2028

O

7.5 595.2 2029

O

6.4 564.2 2030

O

5.7 594.2 2031

O

7.9 571.2 2032

O

6.2 572.2 2033

O

5.3 572.2 2034

O

7.7 601.2 2035

O

7.8 601.2 2036

O

7.8 601.2 2037

O

7.2 601.3 2038

O

5.6 601.3 2039

O

4.9 577.2 2040

O

6.2 578.2 2041

O

5.4 593.2 2042

O

5.9 592.2 2043

O

7.8 591.2 2044

O

7.5 594.2 2045

O

4.9 548.3 2046

O

4.8 522.2 2047

O

4.8 2048

O

4.9 566.3 2049

O

4.7 578.3 2050

O

4.8 578.3 2051

O

5.1 592.3 2052

O

4.8 564.3 2053

O

7.0 546.2 2054

O

7.5 572.2 2055 H O CH₃

6.0 437.2 2056 H S

6.7 481.2 2057

O

5.0 562.2 2058

O

4.9 576.2 2059 H O

6.0 473.1 2060

O

6.9 575.2 2061

O

5.9 562.2 2062

O

6.2 562.2 2063

O

5.5 610.2 2064

O

7.3 589.2 2065

O

7.6 588.2 2066

O

5.1 571.2 2067

O

7.5 606.2 2068

O

6.9 593.2 2069

O

6.1 543.1 2070

O

6.4 571.1 2071

O

5.8 557.1 2072

O

5.2 584.1 2073

O

5.4 591.2 2074 H O

6.0 485.1 2075

O

5.8 636.1 2076

O CH₃

6.5 566.0 2077

O CH₃

5.6 544.1 2078

O CH₃

6.4 544.1 2079

O CH₃

4.8 536.1 2080

O CH₃

5.5 518.1 2081

O CH₃

5.9 518.1 2082 H O

5.6 495.1 2083

O

5.9 604.1 2084

O

7.3 585.2 2085 H O

5.8 522.1 2086 H O

7.0 512.9 2087 H O

6.7 473.1 2088 H O

6.9 537 2089 H O

6.7 522.9 2090 H O

6.6 479 2091 H O

6.5 491 2092 H O

6.8 473.1 2093 H O

7.0 537 2094 H O

6.9 537 2095 H O

6.8 497 2096 H O

6.9 493 2097 H O

6.8 493 2098 H O

6.8 497 2099 H O

6.8 540.9 2100 H O

6.6 477.1 2101

O CH₃

5.6 576.1 2102

O

5.2 577.1 2103

O

6.2 576.1 2104

O

5.4 591.1 2105

O

5.5 605.1 2106

O

6.2 619.1 2107

O

5.5 595.1 2108

O

5.6 596.1 2109 H O

5.6 508.1 2110 H O

5.4 480.1 2111

O

5.9 594.2 2112 H O

5.5 481.1 2113

O

6.9 611.2 2114

O

5.1 580.2 2115

O

6.2 612.2 2116

O

5.3 598.2 2117

O

7.0 598.3 2118

O

5.7 546.2 2119

O

5.2 577.2 2120

O

5.8 572.3 2121

O

5.3 574.3 2122 H O

6.0 494.2 2123 H O

6.6 522.2 2124 H O

6.6 534.2 2125 H O

6.9 536.2 2126 H O

6.9 536.2 2127 H O

7.0 548.2 2128 H O

7.0 548.2 2129 H O

6.2 550.2 2130 H O

5.7 550.3 2131 H O

7.2 550.3 2132 H O

7.1 550.3 2133 H O

5.0 551.3 2134 H O

6.5 552.2 2135 H O

5.6 563.2 2136 H O

5.2 571.2 2137 H O

6.0 578.3 2138 H O

6.2 578.3 2139 H O

6.8 578.3 2140 H O

7.0 580.3 2141 H O

5.9 591.3 2142 H O

5.7 591.3 2143 H O

5.0 591.3 2144 H O

6.3 598.2 2145 H O

7.2 602.2 2146 H O

6.8 570.2 2147 H O

7.0 584.2 2148 H O

7.0 584.2 2149 H O

5.5 553.3 2150 H O

5.2 554.3 2151

O

5.2 572.3 2152

O

5.0 576.3 2153

O

6.7 598.3 2154

O

5.0 578.3 2155

O

5.5 578.2 2156

O

5.8 551.3 2157

O

6.3 572.2 2158

O

6.9 593.3 2159

O

6.4 579.3 2160

O

7.4 594.3 2161

O

6.9 588.3 2162

O

7.1 580.3 2163

O

6.6 552.3 2164

O

5.4 595.3 2165

O

5.4 613.3 2166

O

6.1 565.3 2167

O

6.4 591.3 2168

O

6.7 593.3 2169

O

6.0 588.3 2170

O

5.9 605.3 2171

O

6.0 547.2 2172

O

5.7 547.2 2173

O

6.4 596.3 2174

O

5.0 562.3 2175

O

4.8 640.1 2176

O

6.8 605.2 2177

O

6.7 606.2 2178

O

7.6 605.2 2179

O

7.9 650.2 2180

O

5.9 656.3 2181

O

5.6 546.3 2182

O

6.2 599.3 2183

O

5.7 571.3 2184

O

6.2 572.3 2185

O

5.8 601.3 2186

O

7.2 565.2 2187

O

7.5 579.3 2188

O

7.5 579.3 2189

O

7.8 593.3 2190

O

7.5 605.2 2191

O

5.6 578.2 2192

O

6.3 635.2 2193

O

7.0 559.2 2194

O

4.8 577.3 2195 H O

6.1 543.0 2196 H O

6.1 493.1 2197

O

5.0 561.2 2198

O

5.3 561.2 2199

O

5.0 577.2 2200

O

5.0 571.2 2201

O

5.6 602.2 2202

O

5.1 575.2 2203

O

5.6 563.2 2204

O

6.1 561.1 2205

O

5.1 596.2

1. A compound of formula (I):

wherein: X is selected from O and S; R² is pyridine, optionallysubstituted with 1 to 5 R²⁰ substituents, wherein R²⁰ in each case isindependently selected from: a) halo, cyano or nitro; b) R⁷, —C(═O)—R⁷,—C(═O)—O—R⁷, —O—R⁷, —S—R⁷, —SO—R⁷, —SO₂—R⁷, —(C₁₋₆)alkylene-R⁷,—(C₁₋₆)alkylene-C(═O)—R⁷, —(C₁₋₆)alkylene-C(═O)—O—R⁷,—(C₁₋₆)alkylene-O—R⁷, —(C₁₋₆)alkylene-S—R⁷, —(C₁₋₆)alkylene-SO—R⁷ or—(C₁₋₆)alkylene-SO₂—R⁷; wherein R⁷ is in each instance independentlyselected from H, (C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₂₋₆)alkynyl,(C₁₋₆)haloalkyl, (C₃₋₇)cycloalkyl, aryl and Het; wherein the (C₁₋₆)alkylis optionally substituted with 1 or 2 substituents each independentlyselected from —OH, —O—(C₁₋₆)alkyl, cyano, COOH, —NH₂, —NH(C₁₋₄)alkyl,—NH(C₃₋₇)cycloalkyl, —N((C₁₋₄)alkyl)(C₃₋₇)cycloalkyl and—N((C₁₋₄)alkyl)₂; and wherein each of the aryl and Het is optionallysubstituted with 1 to 3 substituents each independently selected from:i) halo, cyano, oxo, thioxo, imino, —OH, —O—(C₁₋₆)alkyl,—O—(C₁₋₆)haloalkyl, (C₃₋₇)cycloalkyl, (C₁₋₆)haloalkyl,—C(═O)—(C₁₋₆)alkyl, —SO₂(C₁₋₆)alkyl, —C(═O)—NH₂, —C(═O)—NH(C₁₋₄)alkyl,—C(═O)—N((C₁₋₄)alkyl)₂, —C(═O)—NH(C₃₋₇)cycloalkyl,—C(═O)—N((C₁₋₄)alkyl)(C₃₋₇)cycloalkyl, —NH₂, —NH(C₁₋₄)alkyl,—N((C₁₋₄)alkyl)₂, —NH(C₃₋₇)cycloalkyl, —N((C₁₋₄)alkyl)(C₃₋₇)cycloalkylor —NH—C(═O)(C₁₋₄)alkyl; ii) (C₁₋₆)alkyl optionally substituted with—OH, —O—(C₁₋₆)haloalkyl, or —O—(C₁₋₆)alkyl; and iii) aryl or Het,wherein each of the aryl and Het is optionally substituted with halo or(C₁₋₆)alkyl; and c) —N(R⁸)R⁹, —C(═O)—N(R⁸)R⁹, —O—C(═O)—N(R⁸)R⁹,—SO₂—N(R⁸)R⁹, —(C₁₋₆)alkylene-N(R⁸)R⁹, —(C₁₋₆)alkylene-C(═O)—N(R⁸)R⁹,—(C₁₋₆)alkylene-O—C(═O)—N(R⁸)R⁹, or —(C₁₋₆)alkylene-SO₂—N(R⁸)R⁹ whereinR⁸ is in each instance independently selected from H, (C₁₋₆)alkyl and(C₃₋₇)cycloalkyl; and R⁹ is in each instance independently selected fromR⁷, —(C₁₋₆)alkylene-R⁷, —SO₂—R⁷, —C(═O)—R⁷, —C(═O)OR⁷ and —C(═O)N(R⁸)R⁷;wherein R⁷ and R⁸ are as defined above; R³ is selected from H, halo,(C₁₋₄)alkyl, —O—(C₁₋₄)alkyl, —S—(C₁₋₄)alkyl, —NH₂, —NH(C₁₋₄)alkyl,—NH(C₃₋₇)cycloalkyl, —N((C₁₋₄)alkyl)(C₃₋₇)cycloalkyl and—N((C₁₋₄)alkyl)₂; R⁵ is H, (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl or Het; the(C₁₋₆)alkyl and Het each being optionally substituted with 1 to 4substituents each independently selected from (C₁₋₆)alkyl, Het, —OH,—COOH, —C(═O)—(C₁₋₆)alkyl, —C(═O)—O—(C₁₋₆)alkyl, —SO₂(C₁₋₆)alkyl and—C(═O)—N(R⁵¹)R⁵²; wherein R⁵¹ is H, (C₁₋₆)alkyl or (C₃₋₇)cycloalkyl; andR⁵² is H, (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, aryl, Het, aryl-(C₁₋₃)alkyl- orHet-(C₁₋₃)alkyl-; wherein each of the (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl,aryl, Het, aryl-(C₁₋₃)alkyl- and Het-(C₁₋₃)alkyl- are optionallysubstituted with 1 to 3 substituents each independently selected from(C₁₋₆)alkyl, (C₁₋₆)haloalkyl, halo, oxo, —OH, —O(C₁₋₆)alkyl, —NH₂,—NH(C₁₋₆)alkyl, —N((C₁₋₆)alkyl)₂, —NH(C₃₋₇)cycloalkyl,—N((C₁₋₄)alkyl)(C₃₋₇)cycloalkyl, —C(═O)(C₁₋₆)alkyl and—NHC(═O)—(C₁₋₆)alkyl; wherein the (C₁₋₆)alkyl is optionally substitutedwith OH; or R⁵¹ and R⁵², together with the N to which they are attached,are linked to form a 4- to 7-membered heterocycle optionally furthercontaining 1 to 3 heteroatoms each independently selected from N, O andS, wherein each S heteroatom may, independently and where possible,exist in an oxidized state such that it is further bonded to one or twooxygen atoms to form the groups SO or SO₂; wherein the heterocycle isoptionally substituted with 1 to 3 substituents each independentlyselected from (C₁₋₆)alkyl, (C₁₋₆)haloalkyl, halo, oxo, —OH,—O(C₁₋₆)alkyl, —NH₂, —NH(C₁₋₆)alkyl, —N((C₁₋₆)alkyl)₂,—NH(C₃₋₇)cycloalkyl, —N((C₁₋₄)alkyl)(C₃₋₇)cycloalkyl, —C(═O)(C₁₋₆)alkyland —NHC(═O)—(C₁₋₆)alkyl; wherein the (C₁₋₆)alkyl is optionallysubstituted with OH; R⁶ is (C₃₋₇)cycloalkyl or aryl; the(C₃₋₇)cycloalkyl and aryl each being optionally substituted with 1 to 5substituents each independently selected from halo, (C₁₋₆)alkyl,(C₁₋₆)haloalkyl, (C₃₋₇)cycloalkyl, —OH, —SH, —O—(C₁₋₄)alkyl and—S—(C₁₋₄)alkyl; and Het is a 4- to 7-membered saturated, unsaturated oraromatic heterocycle having 1 to 4 heteroatoms each independentlyselected from O, N and S, or a 7- to 14-membered saturated, unsaturatedor aromatic heteropolycycle having wherever possible 1 to 5 heteroatoms,each independently selected from O, N and S; wherein each N heteroatommay, independently and where possible, exist in an oxidized state suchthat it is further bonded to an oxygen atom to form an N-oxide group andwherein each S heteroatom may, independently and where possible, existin an oxidized state such that it is further bonded to one or two oxygenatoms to form the groups SO or SO₂; provided that when R² is selectedfrom:

X is O; R³ is H; and R⁵ is H; then R⁶ is not

or a salt or ester thereof.
 2. A compound according to claim 1 wherein Xis O.
 3. A compound according to claim 1 wherein X is S.
 4. A compoundaccording to claim 1 wherein R² is

optionally substituted with 1 to 3 R²⁰ substituents, wherein R²⁰ is asdefined in claim
 1. 5. A compound according to claim 4 wherein R² is Hetof the formula:

optionally substituted with 1 to 3 R²⁰ substituents; wherein R²⁰ isselected from: a) halo or cyano; b) R⁷, —(C₁₋₆)alkylene-R⁷, —C(═O)—R⁷,—(C₁₋₆)alkylene-O—R⁷, —SO₂—R⁷, —(C₁₋₆)alkylene-S—R⁷ or—(C₁₋₆)alkylene-SO₂—R⁷; wherein R⁷ is in each instance independentlyselected from H, (C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₁₋₆)haloalkyl,(C₃₋₇)cycloalkyl, aryl and Het; wherein the Het is a 5- or 6-memberedheterocycle containing 1 to 4 heteroatoms, each independently selectedfrom N, O and S, or Het is a 9- or 10-membered heteropolycyclecontaining 1 to 4 heteroatoms, each independently selected from N, O andS; wherein each N heteroatom may, independently and where possible,exist in an oxidized state such that it is further bonded to an oxygenatom to form an N-oxide group and wherein each S heteroatom may,independently and where possible, exist in an oxidized state such thatit is further bonded to one or two oxygen atoms to form the groups SO orSO₂; and wherein the (C₁₋₆)alkyl is optionally substituted with 1 or 2substituents each independently selected from —OH, —O—(C₁₋₆)alkyl andCOOH; and wherein each of the aryl and Het is optionally substitutedwith 1 to 3 substituents each independently selected from halo, cyano,oxo, imino, —OH, —O—(C₁₋₆)alkyl, —NH₂, —NH(C₁₋₄)alkyl, —N((C₁₋₄)alkyl)₂,—NH—C(═O)(C₁₋₄)alkyl, (C₁₋₆)alkyl and Het, wherein the Het is a 5- or6-membered heterocycle containing 1 to 4 heteroatoms, each independentlyselected from N, O and S; and c) —(C₁₋₆)alkylene-N(R⁸)R⁹ or—(C₁₋₆)alkylene-C(═O)—N(R⁸)R⁹ wherein R⁸ is in each instanceindependently selected from H and (C₁₋₆)alkyl; and R⁹ is in eachinstance independently selected from R⁷, —SO₂—R⁷, —C(═O)—R⁷, —C(═O)OR⁷and —C(═O)N(R⁸)R⁷; wherein R⁷ and R⁸ are as defined above.
 6. A compoundaccording to claim 1 wherein R² is a group of the formula:

wherein R²³ is R²⁰; and R²⁰ is as defined in claim
 1. 7. A compoundaccording to claim 5 wherein R² is a group of the formula:

wherein R²³ is R²⁰; and R²⁰ is selected from: a) halo or cyano; b) R⁷,—CH₂—R⁷, —C(═O)—R⁷, —CH₂—O—R⁷, —SO₂—R⁷, —CH₂—S—R⁷ or —CH₂—SO₂—R⁷;wherein R⁷ is in each instance independently selected from H,(C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₁₋₆)haloalkyl, (C₃₋₇)cycloalkyl, phenyland Het; wherein the Het is selected from:

wherein the (C₁₋₆)alkyl is optionally substituted with 1 or 2substituents each independently selected from —OH, —O—(C₁₋₆)alkyl andCOOH; and wherein each of the phenyl and Het is optionally substitutedwith 1 to 3 substituents each independently selected from halo, cyano,oxo, imino, —OH, —O—(C₁₋₆)alkyl, —NH₂, —NH(C₁₋₄)alkyl, —N((C₁₋₄)alkyl)₂,—NH—C(═O)(C₁₋₄)alkyl, (C₁₋₆)alkyl and

 and c) —CH₂—N(R⁸)R⁹ or —CH₂—C(═O)—N(R⁸)R⁹ wherein R⁸ is in eachinstance independently selected from H and (C₁₋₆)alkyl; and R⁹ is ineach instance independently selected from R⁷, —SO₂—R⁷, —C(═O)—R⁷,—C(═O)OR⁷ and —C(═O)N(R⁸)R⁷; wherein R⁷ and R⁸ are as defined above. 8.A compound according to claim 6 wherein R² is a group of the formula:

wherein R²³ is R²⁰; and R²⁰ is selected from: b) —CH₂—R⁷, —CH₂CH₂—R⁷,—CH₂—O—R⁷, —CH₂—S—R⁷ or —CH₂—SO₂—R⁷; wherein R⁷ is Het; wherein the Hetis selected from:

wherein the Het is optionally substituted with 1 to 3 substituents eachindependently selected from halo, cyano, oxo, imino, —OH,—O—(C₁₋₆)alkyl, —NH₂, —NH(C₁₋₄)alkyl, —N((C₁₋₄)alkyl)₂,—NH—C(═O)(C₁₋₄)alkyl, (C₁₋₆)alkyl and

 and c) —CH₂—N(R⁸)R⁹ wherein R⁸ is in each instance independentlyselected from H and (C₁₋₆)alkyl; and R⁹ is R⁷ wherein R⁷ is as definedabove.
 9. A compound according to claim 1 wherein R³ is selected from Hand halo.
 10. A compound according to claim 9 wherein R³ is H.
 11. Acompound according to claim 1 wherein R⁵ is (C₁₋₆)alkyl.
 12. A compoundaccording to claim 11 wherein R⁵ is 1-methylethyl.
 13. A compoundaccording to claim 1 wherein R⁵ is (C₁₋₄)alkyl substituted with Het,—COOH or —C(═O)—N(R⁵¹)R⁵², wherein the Het is a 5- or 6-memberedheterocycle containing from 1 to 4 N heteroatoms or Het is a 9- or10-membered bicyclic heteropolycycle containing from 1 to 4 Nheteroatoms; and wherein R⁵¹ is H or (C₁₋₆)alkyl and R⁵² is selectedfrom H, (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, Het and Het-(C₁₋₃)alkyl-; whereinthe (C₁₋₆)alkyl is optionally substituted with 1 or 2 substituents eachindependently selected from —O(C₁₋₆)alkyl and —N((C₁₋₆)alkyl)₂; andwherein the Het and the Het portion of Het-(C₁₋₃)alkyl- are eachindependently a 5- or 6-membered heterocycle containing 1 to 3heteroatoms each independently selected from N, O and S, wherein the Hetand the Het-(C₁₋₃)alkyl- are each optionally substituted with 1 to 3substituents each independently selected from halo, oxo, —OH,(C₁₋₆)alkyl, (C₁₋₆)haloalkyl, —(C═O)(C₁₋₆)alkyl, —N((C₁₋₆)alkyl)₂ and—NH(C═O)(C₁₋₆)alkyl, wherein the (C₁₋₆)alkyl is optionally substitutedwith OH; or R⁵¹ and R⁵², together with the N to which they are attached,are linked to form a 4- to 7-membered heterocycle optionally furthercontaining 1 to 3 heteroatoms each independently selected from N, O andS, wherein each S heteroatom may, independently and where possible,exist in an oxidized state such that it is further bonded to one or twooxygen atoms to form the groups SO or SO₂; wherein the heterocycle isoptionally substituted with 1 to 3 substituents each independentlyselected from halo, oxo, —OH, (C₁₋₆)alkyl, (C₁₋₆)haloalkyl,—(C═O)(C₁₋₆)alkyl, —N((C₁₋₆)alkyl)₂ and —NH(C═O)(C₁₋₆)alkyl, wherein the(C₁₋₆)alkyl is optionally substituted with OH.
 14. A compound accordingto claim 1 wherein R⁶ is (C₃₋₇)cycloalkyl optionally substituted with 1to 5 substituents each independently selected from halo, (C₁₋₆)alkyl,(C₁₋₆)haloalkyl, (C₃₋₇)cycloalkyl, —OH, —SH, —O—(C₁₋₄)alkyl and—S—(C₁₋₄)alkyl.
 15. A compound according to claim 14 wherein R⁶ is


16. A compound according to claim 1 wherein R⁶ is aryl optionallysubstituted with 1 to 5 substituents each independently selected fromhalo, (C₁₋₆)alkyl, (C₁₋₆)haloalkyl, (C₃₋₇)cycloalkyl, —OH, —SH,—O—(C₁₋₄)alkyl and —S—(C₁₋₄)alkyl; provided that when R² is selectedfrom:

X is O; R³ is H; and R⁵ is H; then R⁶ is not


17. A compound according to claim 16 wherein R⁶ is phenyl optionallysubstituted with 1 to 3 substituents each independently selected fromhalo, (C₁₋₄)alkyl, (C₃₋₇)cycloalkyl and —S—(C₁₋₄)alkyl; provided thatwhen R² is selected from:

X is O; R³ is H; and R⁵ is H; then R⁶ is not


18. A compound according to claim 1, or a pharmaceutically acceptablesalt or ester thereof; as a medicament.
 19. A pharmaceutical compositioncomprising a therapeutically effective amount of a compound according toclaim 1, or a pharmaceutically acceptable salt or ester thereof; and oneor more pharmaceutically acceptable carriers.
 20. The pharmaceuticalcomposition according to claim 19 additionally comprising at least oneother antiviral agent.
 21. A method of treating a hepatitis C viralinfection in a mammal having or at risk of having the infection, themethod comprising administering to the mammal a therapeuticallyeffective amount of a compound according to claim 1, a pharmaceuticallyacceptable salt or ester thereof, or a composition thereof.
 22. A methodof treating a hepatitis C viral infection in a mammal having or at riskof having the infection, the method comprising administering to themammal a therapeutically effective amount of a combination of a compoundaccording to claim 1 or a pharmaceutically acceptable salt or esterthereof, and at least one other antiviral agent; or a compositionthereof.